JP6858174B2 - Peptide inhibitors of the interleukin 23 receptor, and their use for treating inflammatory diseases - Google Patents

Description

Cross-reference to related applications This application claims priority to US Application Nos. 14 / 800,627 filed on July 15, 2015 and is a continuation of the above application. This application also applies to International Patent Application No. PCT / US2015 / 040658 filed on July 15, 2015, US Provisional Application No. 62 / 264,820 filed on December 8, 2015, and 2016. Claims priority to US Provisional Application No. 62 / 281,123 filed on January 20. All of these applications are incorporated herein by reference in their entirety.

Sequence Listing This application contains a sequence listing that is submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy that was created in 201 7 December 26th, PRTH _ 002 _ 03WO_S T25. It is named txt and has a size of 808 KB.

The present invention relates to novel peptide inhibitors of the interleukin 23 receptor and their use for treating or preventing a variety of diseases and disorders, including inflammatory bowel disease, Crohn's disease and psoriasis.

Interleukin 23 (IL-23) cytokines are used in autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD), such as ulcerative colitis. It has been considered to play a vital role in the etiology of inflammation and Crohn's disease. Studies in acute and chronic mouse models of IBD have revealed the major roles of IL-23R and downstream effector cytokines in the cause of disease. IL-23R is a variety of adaptive immune cells and native immunity found in large numbers in the intestine, including Th17 cells, γδ T cells, natural killer (NK) cells, dendritic cells, macrophages, and native lymphocytic cells. Expressed on cells. It has been found that IL-23R gene expression and protein levels on the surface of the intestinal mucosa are elevated in IBD patients. IL-23 is thought to mediate this effect by promoting the development of ^{pathogenic CD4 +} T cell populations that produce IL-6, IL-17, and tumor necrosis factor (TNF).

IL-23 production is abundant in the intestine, where with tolerance through the T cell-dependent and T-cell-independent pathways of intestinal inflammation through its effects on T helper 1 (Th1) cytokines and Th17-related cytokines. It is thought to play an important role in regulating immune balance and suppressing regulatory T cell responses in the gastrointestinal tract, which favors inflammation. In addition, polymorphisms in the IL-23 receptor (IL-23R) have been associated with susceptibility to IBD, further establishing a decisive role for the IL-23 pathway in intestinal homeostasis.

Psoriasis, a chronic skin disease that affects about 2% to 3% of the general population, has been shown to be mediated by the body's T-cell inflammatory reaction mechanism. Il-23 plays an important role in the etiology of psoriasis by maintaining chronic autoimmune inflammation by inducing interleukin-17, regulating T memory cells, and activating macrophages, as expected. It is one of several interleukins that are said to be. IL-23 and IL-23R expression has been shown to be elevated in tissues of psoriasis patients, and in animal models of psoriasis, antibodies that neutralize IL-23 are IL-23 dependent on psoriasis development. It showed sexual inhibition.

IL-23 is a heterodimer composed of a unique p19 subunit and a p40 subunit of IL-12, which is responsible for _{the development of interferon-γ (IFN-γ) producing T helper 1 (TH} 1) cells. It is a cytokine involved. Both IL-23 and IL-12 contain the p40 subunit, but differ in phenotypic properties. For example, IL-12-deficient animals are susceptible to inflammatory autoimmune diseases, while IL-23-deficient animals are resistant, which is probably IL-6 in the IL-23-deficient CNS. , IL-17, and due to a decrease in the number of ^{CD4 + T cells producing TNF.} IL-23 binds to IL-23R, a heterodimer receptor composed of the IL-12Rβ1 subunit and the IL-23R subunit. Binding of IL-23 to IL-23R activates the Jak-stat signaling molecules Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, but Stat4 activity compared to IL-12. The formation is substantially weak and different DNA-binding Stat complexes are formed in response to IL-23. IL-23R is constitutively associated with Jak2 and ligand-dependently associated with Stat3. In contrast to IL-12, which acts primarily on naive CD4 (+) T cells, IL-23 acts preferentially on memory CD4 (+) T cells.

Attempts have been made to identify therapeutic moieties that block the IL-23 pathway for use in the treatment of IL-23-related diseases and disorders. Several antibodies that bind to IL-23 or IL-23R have been identified, including ustekinumab, a humanized antibody that binds to IL-23, which is licensed for the treatment of psoriasis. Most recently, a polypeptide inhibitor that binds to IL-23R and inhibits the binding of IL-23 to IL-23R has been identified (see, eg, US Patent Application Publication No. US2013 / 0029907). Clinical practice in Crohn's disease or psoriasis with ustekinumab and briaquinumab (targeting a common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (targeting a p19 subunit unique to IL-23) The study highlights the potential of IL-23 signaling blockade in the treatment of human inflammatory diseases. Although these findings are promising, they can be used to treat intestinal inflammation, such as Crohn's disease, ulcerative colitis and intestinal diseases including related disorders (intestinal bowel disease), in the intestine. Challenges remain regarding the identification of stable and selective agents that preferentially target the IL-23 pathway.
There is still a need in the art for new therapeutic agents that target the IL-23 pathway, which can be used to treat and prevent IL-23-related diseases, including those associated with autoimmune inflammation in the intestinal tract. It is clear that it has been done. In addition, compounds and methods for specifically targeting IL-23R from the luminal side of the gastrointestinal tract can provide therapeutic benefits to IBD patients suffering from local inflammation of intestinal tissue. The present invention addresses these needs by binding to IL-23R and inhibiting IL-23 binding and signal transduction, providing novel peptide inhibitors suitable for oral administration.

U.S. Patent Application Publication No. 2013/0029907

The present invention provides, among other things, novel peptide inhibitors of IL-23R and related uses.
In a first aspect, the invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof, of formula (Xa):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Xa) (SEQ ID NO: 1354)
(During the ceremony,
X1, X2 and X3 are any amino acids or are absent;
X4 is any amino acid or chemical moiety capable of forming a bond with X9;
X5, X6, X7 and X8 are arbitrary amino acids;
X9 is any amino acid or chemical moiety capable of forming a bond with X4;
X10, X11, X12, X13, X14 and X15 are arbitrary amino acids;
X16, X17, X18, X19 and X20 are any amino acids or are absent)
Contains the amino acid sequence of;
It is cyclized by the bond between X4 and X9,
Provided are peptide inhibitors that inhibit the binding of interleukin 23 (IL-23) to the IL-23 receptor.

In certain embodiments of Xa,

X1 is absent; X2 is absent; X3 is absent; X4 is Cys, Abu or Pen; X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab , Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr; X6 is Asp or Thr; X7 is Trp or 6-chloro- Trp; X8 is Glu, Gln or Val; X9 is Cys, Abu or Pen; X10 is 2-Nal, Phe analog, Tyr, or Tyr analog; X11 is 1 -Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl ₂ ), Trp or Tyr (3-tBu); X12 is 3-Pal, Accc , Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa , D-Asn, Glu, His, hLeu, hArg, Lys, Leu, Octgly, Orn, 4-amino-4-carboxy-piperidin, Arg, Ser, Thr or THP; X13 is Cit, Asp, Dab, Dap, Ph, His, Dap (Peg2-Ac), Dap (pyroglutamic acid), Glu, Homo Arg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA) ), Lys (Peg4-isoGlu-Palm), Lys (pyroglutalic acid), Lys (succinic acid), Asn, Orn, Gln, Arg, Thr or Val; X14 is Asp, Dab (Ac), Dap ( Ac), Ph, His, Lys (Ac), Met, Asn (isobutyl), Gln, Arg, Tyr or Asp (1,4-diaminobutane); X15 is Ala, βAla, Glu, Gly, Asn, Gln, Arg or Ser.

In certain embodiments of Xa, X1 is absent; X2 is absent; X3 is absent; X4 is Cys, Abu or Pen; X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr; X6 is Asp or Thr; X7 is Trp or 6-chloro -Trp; X8 is Gln or Val; X9 is Cys, Abu or Pen; X10 is 2-Nal, Phe analog, Tyr, or Tyr analog; X11 is 1- Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxy Trp, Phe (3,4-Cl ₂ ), Trp or Tyr (3-tBu); X12 is 3-Pal, Accc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa, D-Asn, His, hLeu, hArg, Lys, Leu, Octgly, Orn, 4-amino-4-carboxy-piperidin, or THP; X13 is Cit, Asp, Dab, Dap, Ph, His, Dap ( Peg2-Ac), Dap (pyroglutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (Peg4-isoGlu-Palm), Lys (Pyroglutaric acid), Lys- (succinic acid), Asn, Orn, Gln, Arg, Thr or Val; X14 is Dab (Ac), Dap (Ac), Ph, His, Lys (Ac), Met, Asn, Gln, Arg, or Tyr; X15 is Ala, Beta Ala, Gly, Asn, Gln, or Ser.

In certain embodiments of Xa, X1 is absent; X2 is absent; X3 is absent; X4 is Cys, Abu or Pen; X5 is Dap, Dap (Ac). , Gly, Lys, Gln, Arg, Ser, Thr or Asn; X6 is Thr; X7 is Trp or 6-chloro-Trp; X8 is Gln; X9 is Cys, Abu Or Pen; X10 is 2-Nal, Phe analog, Tyr, or Tyr analog; X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), Phe (3,4) -Cl ₂ ), or Trp; X12 is Acpc, Acbc, Acvc, Acch, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer. , Α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg or THP; X13 is Cit, Asp, Dap, Dap (Peg2-Ac), Dap (pyroglutaric acid), Glu, hArg, Lys, Lys. (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (Peg4-isoGlu-Palm), Lys (pyroglutaric acid), Lys- (succinic acid), Asn, Orn, Gln, Arg, or Val; X14 is Dab (Ac), Dap (Ac), His, Lys (Ac), Asn, Gln, or Tyr; X15 is Ala, Beta Ala, Gly, Asn, Gln, Or Ser.

In certain embodiments of Xa, X1 is absent; X2 is absent; X3 is absent; X4 is Cys, Abu or Pen; X5 is Dap, Dap (Ac). , Gln, Ser, Thr or Asn; X6 is Thr; X7 is Trp; X8 is Gln; X9 is Cys, Abu or Pen; X10 is a Phe analog, Tyr, or Tyr analog; X11 is 2-Nal or Trp; X12 is Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α -MeLeu, α-MeOrn, α-MeSer, α-MeVal, hLeu, Leu, or THP; X13 is Cit, Asp, Glu, Lys, Lys (Ac), Asn, or Gln; Dab (Ac), Asn, or His; X15 is Ala, Beta Ala, Gly, Asn, or Gln.

In certain embodiments of Xa, X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-. Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloropropanoic acid, 4-chlorobutyric acid, 3- Chloroisobutyric acid, Abu, β-azido-Ala-OH, propargylglycine, 2- (3'-butenyl) glycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine , 2- (5'-hexenyl) glycine, or Abu; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or the corresponding α-methyl amino acid of any of the above. Type; X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, Asp, Leu, Val, Phe, or Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-Pentenyl) glycine, Ala, hCys, Abu, Met, MeCys, (D) Tyr or 2- (5'-hexenyl) glycine; X10 is Tyr, Phe (4-OMe), 1-Nal , 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, The (4-CONH ₂ ), The (4-phenoxy), Thr, Tic, Tyr (3-tBu), The (4-tBu), The (4-CN), The (4-Br), The (4) -NH ₂ ), Phe (4-F), Phe (3,5-F ₂ ), Phe (4-CH ₂ CO ₂ H), Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), Phe (4-OCH ₃ ), Bip, Cha, 4-Pyridylalanine, βhTyr, OctGly, Phe (4-N ₃ ), Phe (4-Br), Phe [4- (2) -Aminoethoxy)] or Phe, Phe analogs, It is a Tyr analog, or the corresponding α-methylamino acid type of any of those described above; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ). , Ph (3,4-F ₂ ), Ph (4-CO ₂ H), βhPhe (4-F), α-Me-Trp, 4 _{-Phenylcyclohexyl, Ph (4-CF 3} ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7) -Tri-tert-butyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanizino, Phe (4-OBzl), Octgly, Glu (Bzl), 4-Phenylalanine, Phe [4- (2-aminoethoxy)], 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norhalman, Phe (4-) CONH ₂ ), Phe (3,4-dimethoxy), Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalanine, Bip, or said above. Is the corresponding α-methylamino acid type of any of the above; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl- Ala, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acvc, Acbc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn , Α-MeSer, α-MeVal, Aib, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, β-Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal, β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle, t-butyl-Gly, or the corresponding α-methyl amino acid type of any of those mentioned above; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Arg, Or. n, Val, βhAla, Lys (Ac), (D) Asn, (D) Leu, (D) Phe, (D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal , Β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tle or Aib, Cit, hArg, Lys, Asn, Orn, Gln, or the corresponding α-methyl amino acid type of any of those described above; X14 is Ph, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, TicβhPhe, Arg, Lys (Ac), His; Dap (Ac), Dab (Ac), Asp, or the corresponding α-methylamino acid type of any of the above; X15 is , Gly, Ser, Thr, Gln, Ala, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Thr, Aea, Asp, Asn, Glu, Phe , Gly, Lys, Leu, Pro, Arg, β-Ala, Sarc, or the corresponding α-methylamino acid type of any of those described above; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba. , Gly, Ser, Pro, Asn, Thr, or absent, or the corresponding α-methylamino acid type of any of those described above; X17 is Leu, Lys, Arg, Glu, Ser, Gly, It is the corresponding α-methylamino acid type of either Gln or absent, or those described above.

In certain embodiments of the peptide inhibitor of Xa, the bond is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.

In certain embodiments of the peptide inhibitor of Xa, X4 is Cys, X9 is Cys, and the bond is a disulfide bond. In certain embodiments, X4 is a Pen, X9 is a Pen, and the bond is a disulfide bond. In certain embodiments, X7 is Trp; X10 is Phe, Tyr, Phe analog, or Tyr analog; X11 is Trp, 1-Nal or 2-Nal; X12 is. Aib, α-Me-Lys, a-Me-Leu, Achc, Acvc, Acpc, Acbc or THP. In certain embodiments, X7 is Trp; X10 is Phe, Tyr, Phe analog, or Tyr analog; X11 is Trp, 1-Nal or 2-Nal; X12 is. Aib, α-Me-Lys or a-Me-Leu. In certain embodiments, the peptide inhibitor has the following amino acid sequence: Pen-Q-T-W-Q-Pen- [Phe (4-OMe)]-[2-Nal]-[α-Me-Lys]. -E-N-G (SEQ ID NO: 254) ; Pen-N-T-W-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[ Lys (Ac)] -N-N (SEQ ID NO: 255) ; Pen-Q-T-W-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α -MeLeu]-[Lys (Ac)]-N-N (SEQ ID NO: 256) ; or Pen-Q-T-W-Q- [Pen]-[Phe (4-CONH ₂ )]-[2-Nal] -[Α-MeLys]-[Lys (Ac)]-NN (SEQ ID NO: 257) is included, and the peptide inhibitor contains a disulfide bond between two Pen amino acids.

In certain embodiments of the peptide inhibitor of Xa, X4 has an amino acid, an aliphatic acid, an alicyclic acid or a modified 2-methyl aromatic having a carbon side chain capable of forming a thioether bond with X9. It is an acid; X9 is a sulfur-containing amino acid capable of forming a thioether bond with X4, and the bond between X4 and X9 is a thioether bond. In certain embodiments, X4 is Abu, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propaneic acid, 4-chloro-butyric acid, 3-chloro. -Isobutyric acid; X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys, or D-hCys. In certain embodiments, X4 is Abu; X9 is Cys. In certain embodiments, X7 is Trp; X10 is a Ph, Tyr, Phe analog, or Tyr analog; X11 is Trp, 1-Nal or 2-Nal; X12 is. α-Me-Lys, α-Me-Leu, α-Me-Ser, α-Me-Val, Achc, Acvc, Acpc, Acbc, or [4-amino-4-carboxy-tetrahydropyran]. In certain embodiments, X7 is Trp; X10 is a Ph, Tyr, Phe analog, or Tyr analog; X11 is Trp, 1-Nal or 2-Nal; X12 is. α-Me-Lys or [4-amino-4-carboxy-tetrahydropyran]. In certain embodiments, the peptide inhibitor has the following amino acid sequence: [Abu] -Q-T-W-Q-C- [Phe (4-OMe)]-[2-Nal]-[α-MeLys]. -E-N-G (SEQ ID NO: 258) ; [Abu] -Q-T-W-Q-C- [Phe (4- (2-aminoethoxy))]-W- [α-MeLys] -E- NG (SEQ ID NO: 259) ; or [Abu] -Q-T-W-Q-C- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-amino-4 -Carboxy-tetrahydropyran] -E-N-N (SEQ ID NO: 260) , the peptide inhibitor comprises a thioether bond between Abu and C.

In certain embodiments of the peptide inhibitor of Xa, X4 is Pen, Cys or hCys; X5 is any amino acid; X6 is any amino acid; X7 is Trp, Bip, Gln. , His, Glu (Bzl), 4-Phenylvalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3,4-Cl ₂ ), Phe (4-OMe), 5-Hydroxy-Trp , 6-Chloro-Trp, N-MeTrp, α-Me-Trp, 1,2,3,4-tetrahydro-norhalman, Phe (4-CO ₂ H), Phe (4-CONH ₂ ), Phe (3, 4-dimethoxy), Phe (4-CF ₃ ), Phe (4-tBu), ββ-diPheAla, Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or the corresponding α of any of the above. -Methyl amino acid type; X8 is any amino acid; X9 is Pen, Cys or hCys; X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT , (D) Tyr, Glu, Ph, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, Phe analog or Tyr analog (optionally, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-Guanidino), Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N ₃₎ ), Phe (4-OMe), or Phe (4-OBzl)), or the corresponding α-methylamino acid type of any of those described above; X11 is 2-Nal, 1-Nal, 2,4- Dimethyl Phe, Bip, Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), Phe (4-CO ₂ H), βhPhe (4-F), α-Me-Trp, 4-phenyl Cyclohexyl, Phe (4-CF ₃ ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Ph (4-Me), Trp (2,5,7-tri-tert -Butyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino, Phe (4-OBzl), Octgly, Glu (Bzl), 4-Phenylbenzyl Alanine, Ph [4- (2-aminoethoxy)], 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norhalman, Ph (4-CONH ₂ ), Phe (3,4-OMe ₂ ), Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalanine or Bip, or any of the above. The corresponding α-methyl amino acid type; X12 is α-MeLys, α-MeOrn, α-MeLeu, α-MeVal, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeArg, Ogl , Orn, Pro, Gln, Arg, Ser, Thr or Tle, or the corresponding α-methylamino acid type of any of those described above; X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Ph, Ala, Aib, α-MeLeu, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, Spiro-pip, Thr, Tba, Tlc, Val or Tyr, or any of the above. The corresponding α-methyl amino acid type; X14 is Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, Lys (Ac). ), Orn, or the corresponding α-methylamino acid type of any of those described above; X15 Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Ph, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, Arg, or the corresponding α-methylamino acid type of any of those mentioned above; X16 is absent or Gly, Ala, Asp, Ser, Pro, Asn or Thr, or the corresponding α-methyl amino acid type of any of the above; X17 is absent, Glu, Ser, Gly or Gln, or the corresponding α-methyl amino acid type of any of the above. X18 is absent or any amino acid; X19 is absent or any amino acid; X20 is absent or any amino acid. In certain embodiments, the bond between X4 and X9 is a disulfide bond. In certain embodiments, X1, X2, and X3 are absent. In certain embodiments, X17, X19 and X20 are absent. In certain embodiments, one or both of X4 and X9 are Pens. In certain embodiments, both X4 and X9 are Pens. In certain embodiments, X18 is (D) -Lys. In certain embodiments, the peptide inhibitor is: X5 is Arg, Asn, Gln, Dap, Orn; X6 is Thr or Ser; X7 is Trp, 2-Nal, 1 -Nal, Phe (4-O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (Bzl) or Phe (4-Me), 5-hydroxy-Trp, Being 6-chloro-Trp, N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norhalman; and X8 being one of Gln, Val, Ph, Glu, Lys Includes two or more, three or more, or four. In certain embodiments, the peptide inhibitors are as follows: X10 is Tyr, Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl ₂ ). , Phe (4-tBu), Phe (4-NH ₂ ), Phe (4-Br), Phe (4-CN), Phe (4-CO ₂ H), Phe (4- (2 aminoethoxy)) or Being Ph (4-guanadino); X11 is Trp, 2-Nal, 1-Nal, Phe (4-O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino) ), Phe (Bzl) or Phe (4-Me), 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norhalman; Is Arg, α-MeLys, α-MeLeu, Aib or α-MeOrn; X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn; X15 is Gly , Sr or Ala; and X16 is one or more of non-existent or AEA, two or more, three or more, four or more, five or more, six or more, or seven. including. In certain embodiments, X4 and X9 are Pen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Tyr, Phe. (4-OMe) or 2-Nal; X11 is Trp, 2-Nal or 1-Nal; X12 is Arg, αMeLys or α-MeOrn; X13 is Lys, Glu or Lys (Ac) ); X14 is Ph or Asn; X15 is Gly; X16 is absent. In certain embodiments, one or more of X1, X2 and X3 are absent; one or more of X17, X18, X19 and X20, two or more, three or more, or four. not exist.

In certain embodiments of the peptide inhibitor of Xa, X4 is Abu, Pen, or Cys; X7 is Trp, Bip, Gln, His, Glu (Bzl), 4-Phenylalanine, Tic, Phe. [4- (2-Aminoethoxy)], Phe (3,4-Cl ₂ ), Phe (4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1, 2,3,4-Tetrahydro-norhalman, Ph (4-CO ₂ H), Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), ββ-diPheAla, Phe ( 4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or the corresponding α-methylamino acid type of any of those described above; X9 is Abu, Pen, or Cys; X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, The corresponding α-methyl amino acid form of either the Phe analog or Tyr analog, or those described above; X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu (Bzl), 4-Phenylalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), βhPhe (4-F) ), Phe (4-OMe) , 5- hydroxy -Trp, 6- chloro -Trp, N-MeTrp, α- MeTrp, 1,2,3,4- tetrahydro - _{norharman, Phe (4-CO 2 H} ), Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F) ), 4-Phenylalanine alanine, α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Bip, Nva (5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe (4-Me), Trp ( 2,5,7-Tri-tertbutyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl), or O It is ctgly, or the corresponding α-methylamino acid type of any of those described above; X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) ) Leu, (D) Asp, (D) Ph, (D) Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Grn, Arg, Ser, Thr or Tru, or The corresponding α-methylamino acid type of any of the above; X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α- MeLeu, βAla, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethylGly, Glu, Phe, hLeu, Lys, Leu, As , Pro, Gln, Asp, Arg, Ser, Spiro-pip, Thr, Tba, Tlc, Val or Tyr, or the corresponding α-methylamino acid type of any of those described above; X14 is Asn, Glu, Phe. , Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or the corresponding α-methylamino acid type of any of those described above; X15 is Gly, ( D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Grn , Arg or Ser, or the corresponding α-methylamino acid type of any of those described above, or X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu. , (D) Ph, (D) Thr, Ala, Asn, Ser, AEA, Asp, Glu, Ph, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or the corresponding α- of any of the above. Methyl amino acid type; X16 is absent or Gly, Ala, Asp, Ser, Pro, Asn Alternatively, Thr, or the corresponding α-methyl amino acid type of any of the above; X17 is absent or of the corresponding α-methyl amino acid type of Glu, Ser, Gly or Gln, or any of the above. is there. In certain embodiments, the peptide inhibitor is cyclized by an intramolecular bond between X4 and X9. In certain embodiments, one or more of X1, X2, and X3 are absent. In certain embodiments, one or more of X17, X19 and X20 are absent. In certain embodiments, one of X4 or X9 is Abu and the other of X4 or X9 is not Abu. In certain embodiments, the peptide inhibitor is: X5 is Arg, Gln, Dap or Orn; X6 is Thr or Ser; X7 is Trp, 2-Nal, 1-Nal. , Phe (4-O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl), Phe (4-Me), 5-hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, or α-MeTrp, 1,2,3,4-tetrahydro-norhalman; and X8 is one of Gln, Val, Ph, Glu or Lys. Includes one or more, two or more, three or more, or four. In certain embodiments, the peptide inhibitors are as follows: X10 is Tyr, Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl ₂ ). , Phe (4-tBu), Phe (4-NH ₂ ), Phe (4-Br), Phe (4-CN), Phe (4-CO ₂ H), Phe (4- (2 aminoethoxy)) or Being Ph (4-guanadino); X11 is Trp, 2-Nal, 1-Nal, Phe (4-O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino) ), Phe (Bzl) or Phe (4-Me), 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, α-MeTrp or 1,2,3,4-tetrahydro-norhalman; Is Arg, hLeu, (D) Asn, Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Glu or Lys (Ac); X14 is Phe or Asn. Being; X15 is Gly, Ser or Ala, or X15 is Asn, Gly, Ser, βAla or Ala; and X16 is one or more of non-existent or AEA. Includes 2, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, or 7.

In any particular embodiment of the peptide inhibitor, X4 and X9 are Pens. In certain embodiments, X4 and X9 form a disulfide bond.

In certain embodiments, X4 is Abu and X9 is Cys. In certain embodiments, X4 and X9 form a thioether bond.
In certain embodiments, the peptide inhibitor comprises the amino acid sequence of any one of SEQ ID NOs: 365-370, 857-1029. In certain embodiments, the peptide inhibitor is cyclized by the binding between X4 and X9, and the peptide inhibitor inhibits the binding of interleukin 23 (IL-23) to the IL-23 receptor. ..

In certain embodiments of the peptide inhibitor of Xa, the peptide inhibitor is of formula (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg). And the amino acid sequence described in any of (Vh).

In certain embodiments of the peptide inhibitor of Xa, the peptide inhibitor has the following amino acid sequence:
[Palm]-[IsoGlu]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NNNH ₂ (SEQ ID NO: 1115) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-isoGlu-Palm)]-NN-NH ₂ (SEQ ID NO: 1116) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (Ac)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1117) ) ;
[Octanyl]-[IsoGlu]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ (SEQ ID NO: 1118) ;
[Octanyl]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ (SEQ ID NO: 1119) ;
[Palm]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ (SEQ ID NO: 1120) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-octanyl)]-NN-NH ₂ (sequence) Number 1121) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-Palm)]-NN-NH ₂ (sequence) Number 1122) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-Palm)]-[2-Nal]-[Aib]-[Lys (Ac)] NN-NH ₂ (SEQ ID NO: 1123) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-lauryl)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ (SEQ ID NO: 1124) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-Palm)-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1125) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-lauryl)]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1126) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-isoGlu-Palm)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1127) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-isoGLu-lauryl)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1128) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-isoGlu-Palm)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1129) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-isoGlu-lauryl)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1130) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (IVA)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1131) ) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (biotin)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1132) ) ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (octanyl)]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1133) ) ;
Ac- [Pen]-[Lys (IVA)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ (SEQ ID NO: 1134) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (IVA)]-N −NH ₂ (SEQ ID NO: 1135) ;
Ac- [Pen]-[Lys (biotin)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ (SEQ ID NO: 1136) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (biotin)]-N -NH ₂ (SEQ ID NO: 1137) ;
Ac- [Pen]-[Lys (octanyl)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ (SEQ ID NO: 1138) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (octanyl)]-N -NH ₂ (SEQ ID NO: 1139) ;
Ac- [Pen]-[Lys (Palm)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1140) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-Lys (Palm)]-N- NH ₂ (SEQ ID NO: 1141) ;
Ac- [Pen]-[Lys (PEG8)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1142) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (PEG8)]-N −NH ₂ (SEQ ID NO: 1143) ;
Ac- [Pen] -K (Peg11-Palm) TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ (SEQ ID NO: 1144) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Peg11-palm) ] -N-NH ₂ (SEQ ID NO: 1145) ;
Ac- [Pen]-[Cit] -TW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1146) ;
Ac- [Pen]-[Lys (Ac)]-TW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ (SEQ ID NO: 1147) ;
Ac- [Pen] -NT- [Phe (3,4-OCH3) 2] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[ Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1148) ;
Ac- [Pen] -NT- [Phe (2,4-CH3) 2] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[ Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1149) ;
Ac- [Pen] -NT- [Phe (3-CH3)]-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ (SEQ ID NO: 1150) ;
Ac- [Pen] -NT- [Phe (4-CH3)]-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ (SEQ ID NO: 1151) ;
Ac [(D) Arg]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [ΒAla] -NH ₂ (SEQ ID NO: 1152) ;
Ac-[(D) Tyr]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N -[ΒAla] -NH ₂ (SEQ ID NO: 1153) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-QN-NH ₂ (SEQ ID NO: 1154) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-N -NH ₂ (SEQ ID NO: 1155) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Lys (Ac)] -NH ₂ (SEQ ID NO: 1156) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-QQ-NH ₂ (SEQ ID NO: 1157) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-Q- [βAla] -NH2 ( SEQ ID NO: 1158) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Cit] -NH ₂ (SEQ ID NO: 1159) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit] -NNH ₂ (sequence) Number 1160) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit] -Q-NH ₂ (SEQ ID NO: 1161) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit]-[Lys (Ac) )]-NH ₂ (SEQ ID NO: 1162) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-[ Cit] -NH ₂ (SEQ ID NO: 1163) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -QN- [βAla] -NH ₂ (SEQ ID NO: 1164) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -E- [Cit] -Q-NH ₂ (SEQ ID NO: 1165) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Cit]-N- [Cit] -NH ₂ (SEQ ID NO: 1166) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Cit]-Q- [Cit] -NH ₂ (SEQ ID NO: 1167) ;
Ac- [Pen]-[Cit] -TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1168) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1169) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -QNN-NH ₂ (SEQ ID NO: 1170) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -ENQ-NH ₂ (SEQ ID NO: 1171) ;
Ac- [Pen] -GPWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1172) ) ;
Ac- [Pen] -PGWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1173) ) ;
Ac- [Pen] -NTWN- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1174) ) ;
Ac- [Pen] -NSWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1175) ) ;
Ac- [Pen] -N- [Aib] -WQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ (SEQ ID NO: 1176) ;
Ac- [Pen] -NTW- [Aib]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)] N- [Aib] -NH ₂ (SEQ ID NO: 1177) ;
Ac- [Pen] -QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1178) ;
Ac- [Pen]-[Lys (Ac)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)] NNNH ₂ (SEQ ID NO: 1179) ;
Ac- [Pen] -QVWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1180) ) ;
Ac- [Pen] -NT- [2-Nal] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1181) ;
Ac- [Pen] -NT- [1-Nal] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1182) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1183) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1184) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1185) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1186) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1187) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -N- [βAla] -NH ₂ (SEQ ID NO: 1188) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-LN-NH ₂ (SEQ ID NO: 1189) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-GN-NH ₂ (SEQ ID NO: 1190) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH ₂ (SEQ ID NO: 1191) ) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Aib] -N-NH ₂ (SEQ ID NO: 1192) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH ₂ (SEQ ID NO: 1193) ) ;
Ac- [Pen] -NTW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1194) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Tic]-[βAla]- NH ₂ (SEQ ID NO: 1195) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[nLeu]-[βAla]- NH ₂ (SEQ ID NO: 1196) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla] -NH ₂ (SEQ ID NO: 1197) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla] -NH ₂ (SEQ ID NO: 1198) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-W- [βAla] -NH ₂ (SEQ ID NO: 1199) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-S- [βAla] -NH ₂ (SEQ ID NO: 1200) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-L- [βAla] -NH ₂ (SEQ ID NO: 1201) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[AIB]-[βAla] -NH ₂ (SEQ ID NO: 1202) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[N-MeAla]-[ βAla] -NH ₂ (SEQ ID NO: 1203) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2-Nap]-[βAla ] -NH ₂ (SEQ ID NO: 1204) ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [βAla] -NH ₂ (SEQ ID NO: 1205) ;
Ac-[(D) Arg]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -[Lys (Ac)] NNNH ₂ (SEQ ID NO: 1206) ;
Biotin- [PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1269) ;
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1270) ;
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1271) ;
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1272) ;
Ac-E-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1273) ;
Ac-[(D) Asp]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1274) ;
Ac-R-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1275) ;
Inoethoxyy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1276) ;
Ac-F-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1277) ;
Ac-[(D) Phe]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1278) ;
Ac- [2-Nal]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1279) ;
Ac-T-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1280) ;
Ac-L-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1281) ;
Ac-[(D) Gln]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1282) ;
Ac-[(D) Asn]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1283) ;
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)-(PEG4-Alexa488)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN −NH ₂ (SEQ ID NO: 1284) ;
[Alexa488]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]- ENN-NH ₂ (SEQ ID NO: 1285) ;
[Alexa647]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN -NH ₂ (SEQ ID NO: 1286) ;
[Alexa-647]-[PEG4]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino- 4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1287) ;
[Alexa647]-[PEG12]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1288) ; and [Alexa488]-[PEG4]-[(D) Arg] -cyclo [[Abu] -QTWQC]-[Phe Any of [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1289) Including

It is cyclized via a disulfide bond between two Pen residues or by a thioether bond between an Abu residue and a Cys residue, and the binding of interleukin 23 (IL-23) to the IL-23 receptor. Inhibits.

In certain embodiments, any of the peptide inhibitors described herein comprises one or more half-life extension moieties and / or one or more linker moieties conjugated to a peptide inhibitor. In certain embodiments, the half-life extension moiety is conjugated to a peptide inhibitor via one or more linker moieties.

In certain embodiments, any of the peptide inhibitors described herein further comprises a conjugated chemical substituent. In certain embodiments, the conjugated chemical substituents are oleophilic substituents or polymer moieties such as Ac, Palm, GammaGlu-Palm, IsoGlu-Palm, PEG2-Ac, PEG4-isoGlu. -Palm, (PEG) _5- Palm, succinic acid, glutaric acid, pyroglutaric acid, benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin. In certain embodiments, the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da.

In another aspect, the present invention relates to Formula I:
R ^1- X-R ² (I)
Structure,
Or containing a peptide inhibitor, including a pharmaceutically acceptable salt or solvent compound thereof,
In the formula, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, pegs alone or as a spacer of either of those described above. Including version;
R ² is bound, OH or NH ₂ and
X is any of the peptide sequences described herein, eg, Xa, I, Ia-It, II, IIa-IId, III, IIIa-IIIe, IV, IVa-IVb, V, or Va-Vh. Is.

In a related aspect, the invention is a peptide dimer inhibitor of the interleukin 23 receptor, comprising two peptide monomer subunits linked via one or more linker moieties, respectively. Peptide monomer subunits include peptide dimer inhibitors having the sequences or structures described herein. In certain embodiments, one or both of the peptide monomer subunits are cyclized by an intramolecular bond between X4 and X9. In certain embodiments, one or both of the intramolecular bonds are disulfide bonds, thioether bonds, lactam bonds, selenoethers, diselenides, or olefin bonds. In certain embodiments, it is either the linker shown in Table 2 or described herein. In certain embodiments, the linker moiety is a diethylene glycol linker, iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or PEG linker. In certain embodiments, the N-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments, the C-terminus of each peptide monomer subunit is connected by a linker moiety. In certain embodiments, the linker ensures that at least one internal amino acid residue of the peptide monomer subunit and the N-terminal, C-terminal, or internal amino acid residue of the other peptide monomer subunit. It is connected.

In a further related aspect, the invention comprises a polynucleotide comprising a sequence encoding one or both of the peptide inhibitors of the invention, or the peptide monomer subunits of the peptide dimer inhibitors of the invention. The present invention also includes a vector containing the polynucleotide.

In another aspect, the invention comprises a pharmaceutical composition comprising a peptide inhibitor or peptide dimer inhibitor of the invention and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the pharmaceutical composition comprises an enteric coating. In certain embodiments, the enteric coating protects and releases the pharmaceutical composition within the subject's lower gastrointestinal system.

In another aspect, the invention presents, but is not limited to, inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), serum reaction negative arthritis in a subject. Accompanying enteropathy, microscopic colitis, collagen-accumulating colitis, eosinophilic gastroenteritis, colitis associated with radiation or chemotherapy, colitis with congenital immune impairment as seen in leukocyte adhesion deficiency-1 , Chronic granulomatosis, Glycolytic disease type 1b, Hermannski-Padrac syndrome, Celiac-East syndrome, and Whiscot-Aldrich syndrome, ileal pouchitis after rectal colonectomy and ileal anastomosis, gastrointestinal cancer, pancreatitis, insulin For IL-23 signaling, including addictive diabetes, mammary adenitis, celiac inflammation, cholangitis, peri-biliary inflammation, chronic bronchitis, chronic sinusitis, asthma, psoriasis, or implant-to-host disease A method for treating or preventing a related disease, comprising the step of providing a subject with an effective amount of a peptide inhibitor or pharmaceutical composition of the invention. In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In certain embodiments, the peptide inhibitor or peptide dimer inhibitor inhibits the binding of interleukin 23 (IL-23) to the interleukin 23 receptor (IL-23R). In certain embodiments, the pharmaceutical composition is administered to the subject orally, intravenously, peritoneal, intradermally, subcutaneously, intramuscularly, intrathecal, inhaled, vaginalized, sprayed, sublingual, buccal. Provided by parenteral, rectal, intraocular, inhalation, vaginal, or topical routes of administration. In certain embodiments, the pharmaceutical composition is provided orally to treat inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease. In certain embodiments, the pharmaceutical composition is provided to the subject locally, parenterally, intravenously, subcutaneously, intraperitoneally, or intravenously to treat psoriasis. ..

FIG. 1 provides an example of a rat IL-23 dose-response curve measured by the level of IL-17A in a rat splenocyte assay.

FIG. 2 is a graph showing IL-12-dependent production of IFNγ from human PBMCs treated with Compound A or Compound B in the indicated amounts.

FIG. 3 shows the results regarding the DAI value from the 7th day. Statistical analysis of significance was determined using Student's t-test (GraphPad Prism). ^* P <0.05, ^** p <0.01, ^*** p <0.001, ^*** p <0.0001, and the difference was considered significant.

FIG. 4 shows an alignment of the amino acid sequences of human IL23R, mouse IL-23R, rat IL23R, chimpanzee IL-23R, dog IL-23R and bovine IL-23R. Highly conserved amino acid residues are shaded. Regions of mouse IL-23R not found in other IL-23R species are shown, and regions of IL23R to which certain peptide inhibitors of the invention can bind are indicated by dashed lines. FIG. 4 shows an alignment of the amino acid sequences of human IL23R, mouse IL-23R, rat IL23R, chimpanzee IL-23R, dog IL-23R and bovine IL-23R. Highly conserved amino acid residues are shaded. Regions of mouse IL-23R not found in other IL-23R species are shown, and regions of IL23R to which certain peptide inhibitors of the invention can bind are indicated by dashed lines. FIG. 4 shows an alignment of the amino acid sequences of human IL23R, mouse IL-23R, rat IL23R, chimpanzee IL-23R, dog IL-23R and bovine IL-23R. Highly conserved amino acid residues are shaded. Regions of mouse IL-23R not found in other IL-23R species are shown, and regions of IL23R to which certain peptide inhibitors of the invention can bind are indicated by dashed lines.

FIG. 5 is a table outlining the study design for TNBS-induced colitis in rats.

6A-6D show weight relative to colon length (FIG. 6A), colon wall thickness (FIG. 6A) after sham treatment, vehicle treatment, or treatment with the indicated amount of anti-IL23p19 antibody or compound C. Table 6B, macroscopic colon score (Table 6C) or graph showing the abundance of myeloperoxidase (MPO) in the proximal colon extract quantified by ELISA. Values are shown as mean ± SD. Statistical. the significance was evaluated by one-way ^{ANOVA: * ≦ 0.05; ** ≦} 0.01; *** p ≦ 0.001; **** p ≦ 0.0001; ns, not significant. 6A-6D show weight relative to colon length (FIG. 6A), colon wall thickness (FIG. 6A) after sham treatment, vehicle treatment, or treatment with the indicated amount of anti-IL23p19 antibody or compound C. Table 6B, macroscopic colon score (Table 6C) or graph showing the abundance of myeloperoxidase (MPO) in the proximal colon extract quantified by ELISA. Values are shown as mean ± SD. Statistical. the significance was evaluated by one-way ^{ANOVA: * ≦ 0.05; ** ≦} 0.01; *** p ≦ 0.001; **** p ≦ 0.0001; ns, not significant.

FIG. 7 is a photomicrograph of colonic lesions seen in animals after sham treatment (upper left panel) and micrographs of colonic lesions seen in animals after vehicle treatment (upper right panel, transmural inflammation, presence of necrotic tissue). , And a mucosa without crypts), a photomicrograph of colonic lesions seen in animals after anti-IL23p19 antibody (lower left panel), or colons seen in animals after 160 mg / kg / d compound C. A photomicrograph of the lesion (lower right panel, showing that the lesion is confined to the mucosa).

8A-8E show inflammation (FIG. 8A), mucosal necrosis (FIG. 8B), glandular loss after vehicle treatment, treatment with anti-IL23p19 antibody, or treatment with compound C in the indicated amount. FIG. 8C is a graph showing colon wall thickness (FIG. 8D) and histological score (FIG. 8E).

FIG. 9 shows the concentration of Compound C in plasma and proximal colon determined 1 hour after the last PO dosing (left panel), as well as a magnification above IC75 for its activity determined by rat splenocyte assay (left panel). (Center panel), and a graph showing magnification above IC75 for its activity (right panel) as determined by the rat IL23R ELISA assay.

FIG. 10 shows the structure of a particular peptide inhibitor and provides a schematic diagram illustrating typical types of binding between X4 and X9.

11A-11E show pharmacokinetic data for the IL-23R peptide inhibitor peptide 993 (SEQ ID NO: 993). FIG. 11A shows the concentration (nM) of peptide 993 in serum measured at different time points up to 24 hours after oral administration of peptide 993. 11B-11D show concentrations (nM) of peptide 993 in samples taken from Peyer's patches (FIG. 11B), small intestine (FIG. 11C), and colon (FIG. 11D). The dashed line indicates 350 mM. FIG. 11E shows the amount of peptide 993 detected in feces 24 hours after oral administration (% dose). 11A-11E show pharmacokinetic data for the IL-23R peptide inhibitor peptide 993 (SEQ ID NO: 993). FIG. 11A shows the concentration (nM) of peptide 993 in serum measured at different time points up to 24 hours after oral administration of peptide 993. 11B-11D show concentrations (nM) of peptide 993 in samples taken from Peyer's patches (FIG. 11B), small intestine (FIG. 11C), and colon (FIG. 11D). The dashed line indicates 350 mM. FIG. 11E shows the amount of peptide 993 detected in feces 24 hours after oral administration (% dose).

Figures 12A-12D summarize experiments comparing systemic treatment with prednisolone or anti-IL-23p19 neutralizing antibody to treatment with oral administration with peptide 993 in a TNBS model of acute colitis. FIG. 12A shows the change in body weight (percentage) of sham-treated rats, vehicle-treated rats, and peptide 993-treated rats from day 0 to day 7. FIG. 12B shows the ratio of colon weight to colon length (mg / cm) of the colon recovered from rats on day 7. FIG. 12C shows the macroscopic colon score of the colon recovered from the rat on day 7. FIG. 12D shows the sum of histopathological scores for colons obtained from sham-treated rats, vehicle-treated rats, and peptide 993 treated rats. All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant.

Figures 13A-13C summarize experiments comparing systemic treatment with prednisolone or anti-IL-23p19 neutralizing antibody to treatment with oral administration with peptide 1185 in a TNBS model of acute colitis. FIG. 13A shows the change in body weight (percentage) of sham-treated rats, vehicle-treated rats, and peptide 1185-treated rats from day 0 to day 7. FIG. 13B shows the ratio of colon weight to colon length (mg / cm) of the colon recovered from rats on day 7. FIG. 13C shows the macroscopic colon score of the colon recovered from the rat on day 7. All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant.

Figures 14A-14D summarize an experiment comparing systemic treatment with prednisolone or an anti-IL-23p19 neutralizing antibody in a TNBS model of acute colitis with treatment with oral administration with peptide 980. FIG. 14A shows the change in body weight (percentage) of sham-treated rats, vehicle-treated rats, and peptide 980-treated rats from day 0 to day 7. FIG. 14B shows the ratio of colon weight to colon length (mg / cm) of the colon recovered from rats on day 7. FIG. 13C shows the macroscopic colon score of the colon recovered from the rat on day 7. FIG. 14D shows the sum of histopathological scores for colons obtained from sham-treated rats, vehicle-treated rats, and peptide 980-treated rats. All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant.

Figures 15A-15E show disease and IL-23 measured in the colon from rats in the sham (not exposed to TNBS) experimental group treated with vehicle or peptide 993, or in the experimental group exposed to TNBS. Indicates the level of inducible biomarkers. Data for MPO (FIG. 15A), IL-6 (FIG. 15B), IL-1 beta (FIG. 15C), IL-22 (FIG. 15D), and IL-17A (FIG. 15E) are shown. All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant. Figures 15A-15E show disease and IL-23 measured in the colon from rats in the sham (not exposed to TNBS) experimental group treated with vehicle or peptide 993, or in the experimental group exposed to TNBS. Indicates the level of inducible biomarkers. Data for MPO (FIG. 15A), IL-6 (FIG. 15B), IL-1 beta (FIG. 15C), IL-22 (FIG. 15D), and IL-17A (FIG. 15E) are shown. All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant.

16A-16B show diseases and IL-23 measured in the colon from rats in the sham (not exposed to TNBS) experimental group treated with vehicle or peptide 980, or in the experimental group exposed to TNBS. Indicates the level of inducible biomarkers. Data are shown for MPO (FIG. 16A) and IL-22 (FIG. 16B). All experiments were subjected to one-way ANOVA followed by statistical comparisons between groups using post-test: ^* p <0.05; ^** p <0.01; ^*** p <0.001; ^{* ***} p <0.0001; ns, not significant.

17A-17D show sild analysis of inhibitor peptides. FIG. 17A shows peptide 993 at a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence is shown. The characteristics of the curve are listed below the graph. FIG. 17B shows the results from the same set of experiments and shows a graph showing ^{Logs (dose ratio-1) according to peptide 993 concentration (M) on a logarithmic scale.} The characteristics of the obtained linear function are shown below the graph. FIG. 17C shows SEQ ID NO: 1169 with a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence of the peptide of is shown. The characteristics of the curve are listed below the graph. FIG. 17D shows SEQ ID NO: 1211 with a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence of the peptide of is shown. The characteristics of the curve are listed below the graph. 17A-17D show sild analysis of inhibitor peptides. FIG. 17A shows peptide 993 at a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence is shown. The characteristics of the curve are listed below the graph. FIG. 17B shows the results from the same set of experiments and shows a graph showing ^{Logs (dose ratio-1) according to peptide 993 concentration (M) on a logarithmic scale.} The characteristics of the obtained linear function are shown below the graph. FIG. 17C shows SEQ ID NO: 1169 with a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence of the peptide of is shown. The characteristics of the curve are listed below the graph. FIG. 17D shows SEQ ID NO: 1211 with a concentration of 0 nM (black circle), 0.3 nM (black square), 1 nM (triangle), 3 nM (inverted triangle), 10 nM (diamond), 30 nM (white circle), or 100 nM (white square). The graph which shows the% Emax response according to the increasing concentration IL-23 in the presence of the peptide of is shown. The characteristics of the curve are listed below the graph.

18A-18B show pharmacokinetic data for IL-23R peptide inhibitor peptide 1185. FIG. 18A shows the concentration of peptide 1185 in serum and in samples taken from the small intestine and colon. FIG. 18B shows the amount of peptide 1185 detected in urine and feces 24 hours after oral administration (% dose). 18A-18B show pharmacokinetic data for IL-23R peptide inhibitor peptide 1185. FIG. 18A shows the concentration of peptide 1185 in serum and in samples taken from the small intestine and colon. FIG. 18B shows the amount of peptide 1185 detected in urine and feces 24 hours after oral administration (% dose).

19A and 19B show pharmacokinetic data for IL-23R peptide inhibitor peptide 980. FIG. 19A shows the concentration of peptide 980 in serum and in samples taken from the small intestine and colon. FIG. 19B shows the amount of peptide 980 detected in urine and feces 24 hours after oral administration (% dose). 19A and 19B show pharmacokinetic data for IL-23R peptide inhibitor peptide 980. FIG. 19A shows the concentration of peptide 980 in serum and in samples taken from the small intestine and colon. FIG. 19B shows the amount of peptide 980 detected in urine and feces 24 hours after oral administration (% dose).

Unless otherwise defined herein, the scientific and technological terms used in this application shall have meanings commonly understood by those skilled in the art. Nomenclature and techniques commonly used in connection with chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry as described herein. Is well known and commonly used in the art.

As used herein, the following terms have the meaning attributable to them, unless otherwise specified.

Throughout this specification, the word "comprise" or variants such as "comprises" or "comprising" are of the integers (or components) or integers (or components) shown. It should be understood that groups are included, but not all other integers (or components) or groups of integers (or components) are excluded.

The singular forms "one (a)", "one (an)", and "the" include the plural unless explicitly stated otherwise by the context.

The term "inclusion" is used to indicate the meaning of "inclusion but not limited to". "Including" and "including, but not limited to," are used interchangeably.

The terms "patient," "subject," and "individual" can be used interchangeably and refer to either humans or non-human animals. These terms include mammals such as humans, primates, domestic animals (eg, cows, pigs), companion animals (eg, dogs, cats) and rodents (eg, mice and rats).

The term "peptide", as used herein, broadly refers to a sequence of two or more amino acids linked by a peptide bond. The term does not mean a particular length of polymer of amino acids, whether the polypeptide is made using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring. It should be understood that it is not intended to imply or distinguish.

Descriptions that include "sequence identity," "percent identity," "percent homology," or, for example, "a sequence that is 50% identical to," as used herein, are used in nucleotide units across the comparison window. It is the same in amino acid units or refers to a certain degree. Therefore, "percentage of sequence identity" compares two optimally aligned sequences across a comparison window and has the same nucleobase (eg, A, T, C, G, I) or the same in both sequences. Positions where amino acid residues (eg, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Ph, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) are present. Determine the number of matching positions to obtain the number of matching positions, divide the number of matching positions by the total number of positions in the comparison window (ie, window size), and multiply the result by 100 to obtain the percentage of sequence identity. It can be calculated by obtaining.

Calculations of sequence similarity or sequence identity between sequences (these terms are used interchangeably herein) can be performed as follows. To determine the percent identity of two amino acid sequences, or two nucleic acid sequences, the sequences can be aligned for optimal comparison (eg, a first amino acid sequence or nucleic acid for optimal alignment). Gaps can be introduced into one or both of the sequence and the second amino acid sequence or nucleic acid sequence, and non-homologous sequences can be ignored for comparison purposes). In certain embodiments, the length of the reference sequence aligned for comparison is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, even more preferably, of the length of the reference sequence. Is at least 70%, 80%, 90%, 100%. The amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residues or nucleotides as the corresponding position in the second sequence, then those molecules are identical at that position.

Percent identity between two sequences is the same position shared by the two sequences, taking into account the number of gaps that need to be introduced to optimally align the two sequences, and the length of each gap. Is a function of the number of.

Sequence comparisons and determination of percent identity between two sequences can be achieved using mathematical algorithms. In some embodiments, the percent identity between the two amino acid sequences was incorporated into the GAP program within the GCG software package by Needleman and Wunsch, (1970, J. Mol. Biol. 48: 444-453). ) Using the algorithm, using either the Blossum62 matrix or the PAM250 matrix, as well as the gap weights 16, 14, 12, 10, 8, 6, or 4 and the length weights 1, 2, 3, 4, 5, or 6. To decide. In yet another preferred embodiment, the percent identity between the two nucleotide sequences was determined by using the GAP program within the GCG software package. Determined using the CMP matrix and gap weights 40, 50, 60, 70, or 80 and length weights 1, 2, 3, 4, 5, or 6. Another set of exemplary parameters includes a Blossum62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. Percent identity between two amino acid or nucleotide sequences was incorporated into the ALIGN program (version 2.0). Meyers and W.M. It can also be determined using the algorithm of Miller (1989, Cabios, Volume 4, pp. 11-17) using the PAM120 weighted residue table, gap length penalty 12 and gap penalty 4.

The peptide sequences described herein can be used, for example, as "query sequences" to perform searches in public databases to identify other family members or related sequences. Such a search can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (1990, J. Mol. Biol, Vol. 215: pp. 403-10). A BLAST nucleotide search can be performed using the NBLAST program, score = 100, word length = 12, to obtain a nucleotide sequence homologous to the nucleic acid molecule of the invention. A BLAST protein search can be performed using the XBLAST program, score = 50, word length = 3 to obtain an amino acid sequence homologous to the protein molecule of the present invention. For comparison purposes, Gapped BLAST described by Altschul et al. (Nucleic Acids Res. 25: 3389-3402, 1997) can be used to obtain gap-inserted alignments. When using BLAST and Gapped BLAST programs, the initial parameters of the respective programs (eg, XBLAST and NBLAST) can be used.

The term "conservative substitution" as used herein refers to the replacement of one or more amino acids with another biologically similar residue. Examples include the substitution of amino acid residues having similar properties, such as small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids. For example, see the table below. In some embodiments of the invention, one or more Met residues are replaced with norleucine (Nle), which is a bioisostere of Met but is not easily oxidized in contrast to Met. To. Another example of conservative substitution with residues not normally found in endogenous mammalian peptides and proteins is with Arg or Lys, such as ornithine, canavanine, aminoethylcysteine or another basic amino acid. It is a conservative replacement. In some embodiments, one or more cysteines of the peptide analogs of the invention can be replaced with another residue, such as serine. For more information on phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et al., Science 247, pp. 1306-1310, 1990. In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. I: Neutral, hydrophilic, II: Acids and amides, III: Basic, IV: Hydrophobic, V: Aromatic, bulky amino acids.

In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. VI: Neutral or hydrophobic, VII: Acidic, VIII: Basic, IX: Polar, X: Aromatic.

The terms "amino acid" or "arbitrary amino acid" as used herein are naturally occurring amino acids (eg, a-amino acids), unnatural amino acids, modified amino acids, and non. -Natural) Refers to any and all amino acids, including amino acids. The term includes both D-amino acids and L-amino acids. Natural amino acids include those found in nature, such as the 23 amino acids that combine to form peptide chains and form components of vast arrays of proteins. These are predominantly L stereoisomers, but a small number of D-amino acids are present in the bacterial envelope and some antibiotics. Twenty "standard" natural amino acids are listed in the table above. "Non-standard" natural amino acids are pyrrolidine (found in methane-producing organisms and other eukaryotes), selenocysteine (present in many non-eukaryotes and the majority of eukaryotes), and N. -Formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). A "non-natural" or "non-natural" amino acid is a naturally occurring or chemically synthesized non-proteinogenic amino acid (ie, neither naturally encoded nor found in the genetic code). .. Over 140 unnatural amino acids are known and thousands of combinations are possible. Examples of "unnatural" amino acids are β-amino acids (β ³ and β ² ), homo amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear cores. Included are amino acids, diamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Non-natural or non-natural amino acids also include modified amino acids. A "modified" amino acid includes an amino acid that is not naturally present, a group (a group, groups), or an amino acid that has been chemically modified to include a chemical moiety (eg, a natural amino acid). .. According to certain embodiments, the peptide inhibitor comprises an intramolecular bond between two amino acid residues present in the peptide inhibitor. It is understood that the amino acid residues that form the bond are somewhat altered when bound to each other compared to when not bound to each other. Reference to a particular amino acid means to include both the unbound and bound states of that amino acid. For example, the unbound form of the amino acid residue homoserine (hSer) or homoserine (Cl) may take the form of 2-aminobutyric acid (Abu) when involved in the intramolecular binding according to the invention. The present invention includes both a peptide inhibitor containing a crosslink between X4 and X9 and a peptide inhibitor containing no crosslink between X4 and X9, for example, a peptide inhibitor before the formation of a crosslink. As such, the names hSer and Abu shall refer to the same amino acid and are used interchangeably.

In most cases, the names of naturally occurring aminoacyl residues and non-naturally occurring aminoacyl residues used herein are "Nomenclature of α-Amino Acids (Recommendations, 1974)", Biochemistry, Vol. 14 ( No. 2), (1975), according to the nomenclature proposed by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature. To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims differ from these proposals, those names and abbreviations will be apparent to the reader. Some abbreviations useful to describe the invention are defined in Table 1A below.

Throughout the specification, if naturally occurring amino acids are not referred to by their full name (eg, alanine, arginine, etc.), their traditional three-letter or one-letter abbreviations (eg, Ala for alanine). Or A, arginine is referred to as Arg or R). Unless otherwise specified, the three-letter and one-letter abbreviations for amino acids refer to the L-isomer form of the amino acid. The term "L-amino acid" as used herein refers to a peptide of the "L" isomer type, and conversely, the term "D-amino acid" refers to a peptide of the "D" isomer type ( For example, Dasp, (D) Asp or D-Asp; Dphe, (D) Ph or D-Phe). Any L-amino acid residue can be replaced with a D-amino acid-type amino acid residue as long as the desired function of the peptide is retained. D-amino acids are typically shown in lowercase when referred to using the one-letter abbreviation.

In the case of less common or non-naturally occurring amino acids, if not named by their full name (eg, sarcosine, ornithine, etc.), Sar or Sar (sarcosine, ie N-methylglycine), Aib ( α-Aminoisobutyric acid), Dab (2,4-diaminobutanoic acid), Dapa (2,3-diaminopropanoic acid), γ-Glu (γ-glutamic acid), Gaba (γ-aminobutanoic acid), β-Pro (pyrrolidin) -3-carboxylic acid), and 8Ado (8-amino-3,6-dioxaoctanoic acid), Abu (2-aminobutyric acid), βhPro (β-homoproline), βhPhe (β-homophenylalanine) and Bip (β) , Β-diphenylalanine), and Ida (iminodiacetic acid), frequently used three- or four-letter codes are used for the residue.

As will be apparent to those of skill in the art, the peptide sequences disclosed herein are shown from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the peptide. It is the C-terminal of. The sequences disclosed herein incorporate a "Hy-" moiety at the amino terminus (N-terminus) of the sequence and an "-OH" or "-NH ₂ " portion at the carboxy terminus (C-terminus) of the sequence. There is a sequence in which the part is incorporated. In such cases, unless otherwise specified, the N-terminal "Hy-" portion of the sequence represents a hydrogen atom, which is the presence of a free primary or secondary amino group at the N-terminus. On the other hand, the "-OH" or "-NH ₂ " moiety at the C-terminus of the sequence indicates a hydroxy or amino group, which means that there is an _{amide (CONH 2) group at the C-terminus, respectively.} Equivalent to. In each sequence of the invention, the C-terminal "-OH" moiety _{can replace the C-terminal "-NH 2} " moiety, and vice versa.

The term "DRP" as used herein refers to a peptide rich in disulfides.

The term "dimer" as used herein broadly refers to a peptide containing two or more monomer subunits. Certain dimers contain two DRPs. The dimers of the present invention include homodimers and heterodimers. The monomeric subunit of the dimer may be linked at its C-terminal or N-terminal, or may be linked via an internal amino acid residue. Each monomer subunit of the dimer may be linked through the same site, or each may be linked through a different site (eg, C-terminal, N-terminal, or internal site).

The term "NH ₂ ", as used herein, can refer to a free amino group present at the amino terminus of a polypeptide. The term "OH" as used herein can refer to a free carboxy group present at the carboxy terminus of a peptide. In addition, the term "Ac", as used herein, refers to acetyl protection by acylation of the C-terminus or N-terminus of a polypeptide. _{In certain peptides shown herein, NH 2} located at the C-terminus of the peptide represents an amino group.

The term "carboxy" as used herein refers to _{-CO 2 H.}

The term "isostere replacement" as used herein refers to any amino acid or other analog moiety that has similar chemical and / or structural properties to a particular amino acid.

The term "cyclization", as used herein, is linked, such as by forming a disulfide bridge or other similar bond between one portion of the polypeptide molecule and another portion of the polypeptide molecule. Refers to a reaction that forms a closed ring.

The term "subunit", as used herein, refers to one of a pair of polypeptide monomers that bind to form a dimeric peptide composition.

As used herein, the term "linker moiety" broadly refers to a chemical structure capable of linking or binding two peptide monomer subunits to form a dimer.

The term "pharmaceutically acceptable salt", as used herein, is water-soluble or oil-soluble or dispersible and causes disease without undue toxicity, irritation, and allergic reactions. Represents the form of a salt or zwitterion of a peptide or compound of the invention that is suitable for treatment, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. .. The salt can be prepared during the final isolation and purification of the compound, or it can be prepared separately by reacting the amino group with the appropriate acid. Typical acid addition salts include acetate, adipate, alginate, citrate, asparagate, benzoate, benzenesulfonate, bicarbonate, butyrate, gypsum sulfonate, camphorsulfonic acid. Salt, digluconate, glycerophosphate, hemisulfate, heptaneate, hexanate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic acid Salt (icetionate), lactate, maleate, mesitylenate sulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectin Acids, persulfates, 3-phenylpropionates, picrates, pivalates, propions, succinates, tartrates, trichloroacetates, trifluoroacetates, phosphates, glutamates, carbonates Included are hydrogen salts, paratoluene sulfonates, and undecanoates. The amino groups of the compounds of the present invention are methyl chloride, methyl bromide, and methyl iodide, ethyl chloride, ethyl bromide, and ethyl iodide, propyl chloride, propyl bromide, and propyl iodide, and butyl chloride. Butyl bromide, and butyl iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl chloride, decyl bromide, and decyl iodide, lauryl chloride, lauryl bromide, and lauryl iodide, myristyl chloride, It can be quaternized with myristyl bromide and myristyl iodide, as well as steryl chloride, steryl bromide, and steryl iodide; and benzyl bromide and phenethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as oxalic acid, maleic acid, succinic acid. , And organic acids such as citric acid. Appropriately, the pharmaceutically acceptable salt is, for example, a salt selected from among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrates and acetates. Examples of basic salts include alkali metal cations such as sodium or potassium ions, alkaline earth metal cations such as calcium or magnesium ions, and N (R1) (R2) (R3) ( R4) + -type ions (in the formula, R1, R2, R3 and R4 each independently represent hydrogen, optionally substituted C1-6 alkyl or optionally substituted C2-6 alkenyl) and the like. Examples include salts selected among ammonium ions. Examples of related C1-6 alkyl groups include methyl, ethyl, 1-propyl and 2-propyl groups. Examples of C2-6 alkenyl groups that may be relevant include ethenyl, 1-propenyl and 2-propenyl. Other examples of pharmaceutically acceptable salts include "Remington's Pharmaceutical Sciences", 17th Edition, Alphanso R. et al. Gennaro (eds.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions), "Encyclopedia of Pharmaceutical Technology", 3rd edition, JamesInsur NY, USA, 2007, and J.M. Pharm. Sci. Volume 66: Described on page 2 (1977). See also Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Vermut (Wiley-VCH, 2002) for an overview of suitable salts. Other suitable base salts are formed from the bases that form the NOAEL. Typical examples are aluminum salt, arginine salt, benzatin salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumin salt, olamine salt, potassium salt, etc. Examples include sodium salt, tromethamine salt, and zinc salt. Hemi-salts of acids and bases, such as hemi-sulfates and hemi-calcium salts, can also be formed.

The term "N (alpha) methylation" as used herein describes the methylation of the amino acid alphaamine and is also commonly referred to as N-methylation.

The terms "sym methylation" or "Arg-Me-sym" as used herein describe the symmetrical methylation of two nitrogens of the guanidine group of arginine. In addition, the terms "asym methylation" or "Arg-Me-asym" describe the methylation of a single nitrogen of the guanidine group of arginine.

The term "acylated organic compound" as used herein refers to an amino acid or monomer or dimer, eg, the N-terminus of a monomeric subunit before forming a C-terminal dimer. Refers to various compounds with carboxylic acid functionality used for acylation. Non-limiting examples of acylated organic compounds include cyclopropyl acetic acid, 4-fluorobenzoic acid, 4-fluorophenyl acetic acid, 3-phenylpropionic acid, succinic acid, glutaric acid, cyclopentanecarboxylic acid, 3,3. Examples thereof include 3-trifluoropropenic acid, 3-fluoromethylbutyric acid and tetrahydro-2H-pyran-4-carboxylic acid.

The term "alkyl" includes linear or branched, acyclic or cyclic, saturated aliphatic hydrocarbons containing 1 to 24 carbon atoms. Typical saturated linear alkyl includes, but is not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and the like, and the saturated branched alkyl is not limited. , Isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and the like. Typical saturated cyclic alkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, while unsaturated cyclic alkyl includes, without limitation, cyclopentenyl, cyclohexenyl and the like. Be done.

The term "mammal" refers to any mammalian species such as, for example, humans, mice, rats, dogs, cats, hamsters, guinea pigs, rabbits, livestock.

As used herein, a "therapeutically effective amount" of a peptide inhibitor of the invention is IL-23 / IL, including, but not limited to, any of the diseases and disorders described herein. It describes the amount of peptide inhibitor sufficient to treat a -23R-related disease (eg, to reduce the inflammation associated with IBD). In certain embodiments, the therapeutically effective amount achieves the desired benefit / risk ratio applicable to any medical procedure.

Amino acid "analogs", such as "Phe analogs" or "Tyr analogs," mean analogs of the referenced amino acids. Analogs of various amino acids, including Phe analogs and Tyr analogs, are known and are available in the art. In certain embodiments, amino acid analogs, such as Phe analogs or Tyr analogs, contain one, two, three, four or five substitutions as compared to Ph or Tyr, respectively. In certain embodiments, the substitution is on the side chain of the amino acid. In certain embodiments, the Ph analog has a structure Ph (R ² ), in which R ² is Hy, OH, CH ₃ , CO ₂ H, CONH ₂ , CONH ₂ OCH ₂ CH ₂ NH. ₂ , t-Bu, OCH ₂ CH ₂ NH ₂ , phenoxy, OCH ₃ , Oallyl, Br, Cl, F, NH ₂ , N ₃ , or guanadino. In certain embodiments, R ² is CONH ₂ OCH ₂ CH ₂ NH ₂ , OCH ₃ , CONH ₂ , OCH ₃ or CO ₂ H. Examples of Phe analogs are, but are not limited to, hPhe, Phe (4-OMe), α-Me-Phe, hPhe (3,4-dimethoxy), Phe (4-CONH ₂ ), Phe (4-CONH 2), Phe (4-Ome). Phenoxy), Phe (4-guanadino), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-OBzl), Phe (4-NH ₂ ), ΒhPhe (4-) F), Phe (4-F), Phe (3,5 DiF), Phe (CH ₂ CO ₂ H), Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (3,4-) F ₂ ), Phe (4-CF ₃ ), ββ-diPheAla, Phe (4-N ₃ ), Phe [4- (2-aminoethoxy)], 4 _{-Phenylbenzylalanine, Phe (4-CONH 2} ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), Phe (2,3-Cl ₂ ), and Phe (2,3-F ₂ ) can be mentioned. Examples of Tyr analogs include, but are not limited to, hTyr, N-Me-Tyr, Tyr (3-tBu), Tyr (4-N ₃ ) and βhTyr.

IL-23R Peptide Inhibitor Genome-Wide Association Study (GWAS) demonstrated a significant association between the IL-23 receptor (IL-23R) gene and inflammatory bowel disease (IBD). It is suggested that disruption of signaling may be associated with the etiology of the disease. The present invention provides compositions and methods that modulate the IL-23 pathway through selective antagonism of IL-23R by oral treatment with peptides that are stable and confined to gastrointestinal (GI) tissue. .. In various assays that mimic different compartments of the GI environment, novel inhibitory peptides that are uniquely resistant to oxidation / reduction conditions and proteolysis have been identified. Functionally, these peptides strongly neutralize IL-23-mediated signaling in transformed human cell lines and primary human cells. IL-23R binding is selective because these peptides do not block the interaction between IL-6 and IL-6R or antagonize the IL-12 signaling pathway. In addition, these orally delivered peptides are the ratio of weight to colon length, macroscopic colon score, significant reduction in neutrophil infiltration, and equivalent tissue to control anti-IL-23p19 mAb. As shown by histopathology, it is effective in attenuating colitis in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) -induced acute rat model of IBD.

The present invention generally relates to peptides having IL-23R antagonist activity, including both peptide monomers and peptide dimers. In certain embodiments, the present invention demonstrates a new paradigm for treating IBD and other diseases and disorders by oral delivery of an antagonist of IL-23. IBD exhibits local inflammation of the intestinal tissue, and therefore advantageous therapeutic agents act from the luminal side of the intestine, thereby achieving high drug concentrations in the affected tissue and minimizing systemic availability. It will result in improved efficacy and safety compared to systemic methods. Oral administration of the compounds of the invention maximizes drug levels in affected intestinal tissue while limiting circulating drug concentrations, thereby being effective for lifelong treatment of IBD and other diseases and disorders. It is expected to be safe and long-lasting delivery.

In certain embodiments, the present invention relates to various peptides that form cyclized structures through disulfides or other bonds, or peptide dimers, including heteromonomeric or homomonomeric subunits. In certain embodiments, the disulfide or other bond is an intramolecular bond. The cyclization structure of the monomer subunits of peptide monomer inhibitors and peptide dimer inhibitors has been shown to increase the efficacy and selectivity of peptide inhibitors. In certain embodiments, the peptide dimer inhibitor is one or more intermolecular bonds linking the two monomeric peptide subunits within the peptide dimer inhibitor, eg, each peptide monomer. The subunit may contain one intermolecular bridge between two cysteine residues.

The present invention provides a peptide inhibitor that binds to IL-23R, which may be monomeric or dimeric. In certain embodiments, the peptide inhibitor inhibits the binding of IL-23 to IL-23R. In certain embodiments, IL-23R is human IL-23R and IL-23 is human IL-23. In certain embodiments, the peptide inhibitors of the invention have at least 20%, at least 30%, at least 40%, at least 50% binding of IL-23 to IL-23R as compared to a negative control peptide. Reduce by at least 60%, at least 70%, at least 80%, or at least 90%. Methods of determining binding are known in the art and include the ELISA assay described in the accompanying Examples.

In certain embodiments, for example, with respect to inhibition of IL-23 binding to IL-23R (eg, human IL-23 and human IL-23R), the IC50 of the peptide inhibitor of the invention is> 1 mM, < 1 mM, 500 nM to 1000 nM, <500 nM, <250 nM, <100 nM, <50 nM, <25 nM, <10 nM, <5 nM, <2 nM, <1 nM, or <5 mM. Methods of determining activity are known in the art and include any of those described in the accompanying examples.

In certain embodiments, the peptide inhibitors of the invention have increased stability, increased gastrointestinal stability, or simulated intestinal fluid (SIF) as compared to control peptides. ) Or simulated gastric fluid (SGF) and / or increased stability under redox conditions (eg, DTT). In certain embodiments, the control peptide is an unrelated peptide of the same or similar length. In certain embodiments, the control peptide is a peptide that has the same or highly associated amino acid sequence as the peptide inhibitor (eg,> 90% sequence identity). In certain embodiments, the control peptide has the same or highly associated amino acid sequence as the peptide inhibitor (eg,> 90% sequence identity), but, for example, between two amino acid residues within the control peptide. A peptide that does not have a cyclized structure through an intramolecular bond, is not dimerized, or does not contain a conjugate for stabilization. In certain embodiments, the only difference between a peptide inhibitor and a control peptide is that the peptide inhibitor comprises one or more amino acid substitutions in which one or more amino acid residues are introduced into the peptide inhibitor. The point is that the introduced amino residue (s) forms an intrasulfide disulfide or thioether bond with another amino acid residue in the peptide inhibitor. One example of a control against a peptide dimer inhibitor is a monomer having the same sequence as one of the monomer subunits present in the peptide dimer inhibitor. One example of a control against a peptide inhibitor containing a conjugate is a peptide of the same sequence but without the conjugate moiety. In certain embodiments, the control peptide is a peptide corresponding to the region of IL-23 that binds to IL-23R (eg, a naturally occurring peptide).

Methods of determining the stability of a peptide are known in the art. In certain embodiments, for example, the SIF assay is used to determine the stability of a peptide inhibitor, as described in Example 3. In certain embodiments, for example, the SGF assay is used to determine the stability of a peptide inhibitor, as described in Example 3. In certain embodiments, the half-life of a peptide inhibitor (eg, in SIF or SGF or DTT) is when exposed to SIF or SGF or DTT under a given set of conditions (eg, temperature). More than 1 minute, more than 10 minutes, more than 20 minutes, more than 30 minutes, more than 60 minutes, more than 90 minutes, more than 120 minutes, more than 3 hours, or more than 4 hours. In certain embodiments, the temperature is about 25 ° C, about 4 ° C, or about 37 ° C, and the pH is physiological pH, or about pH 7.4.

In some embodiments, the half-life is measured in vitro using any suitable method known in the art, eg, in some embodiments, the stability of the peptides of the invention is determined by the peptides. Is determined by incubating with pre-warmed human serum (Sigma) at 37 ° C. Samples are obtained at various time points, generally up to 24 hours, and the stability of the sample is determined by separating the peptide or peptide dimer from the serum protein and then LC-MS for the presence of the peptide or peptide dimer of interest. Analyze by analyzing using.

In some embodiments, the peptide inhibitors of the invention exhibit improved solubility or improved aggregation properties compared to control peptides. Solubility can be determined by any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility are peptides in various buffers (acetic acid pH 4.0, acetate pH 5.0, Phos / citric acid pH 5.0, Phos). Citric acid pH 6.0, Phos pH 6.0, Phos pH 7.0, Phos pH 7.5, Strong PBS pH 7.5, Tris pH 7.5, Tris pH 8.0, Glycine pH 9.0, water, acetic acid (pH 5.0 and Incubating in (other known in the art) and testing for aggregation or solubility using standard techniques, including, but not limited to, visual precipitation, dynamic. Included are circularly polarized dichroic and fluorescent dyes for measuring light scattering, surface hydrophobicity, and detection of aggregation or fibrillation. In some embodiments, improved solubility is a peptide. Means that the solubility of a peptide in a given liquid is higher than that of a control peptide. In some embodiments, improved aggregation is in a given liquid of the peptide under a given set of conditions. Means less aggregation in than control peptides.

In certain embodiments that are advantageous for achieving high compound concentrations in intestinal tissue when delivered orally, the peptide inhibitors of the invention are stable in the gastrointestinal (GI) environment. Proteolytic metabolism in the gastrointestinal tract is driven by enzymes secreted from the pancreas into the lumen or produced as brush border enzymes, including pepsin, trypsin, chymotrypsin, elastase, aminopeptidase, and carboxypeptidase A / B. Will be done. Proteases generally cleave stretched conformational peptides and proteins. In the reducing environment of intestinal juice, disulfide bonds can be disrupted, resulting in linear peptides and rapid proteolysis. The redox environment of this lumen is primarily determined by the Cys / CySS redox cycle. In enterocytes, the associated activity includes a number of digestive enzymes such as CYP450 and UDP-glucuronsil-transferase. Finally, another metabolic barrier is constructed by the bacteria present in the large intestine at ^{concentrations ranging from 10 10} CFU / ml to 10 ^{12 CFU / ml.} In certain embodiments, peptide inhibitors tend to go from strong acidity in the stomach (pH 1.5-1.9) to basicity in the small intestine (pH 6-7.5) and weak acidity in the colon (pH 5-5). It is stable against various pH up to 7). Such peptide inhibitors are stable during the passage of various GI compartments, a process estimated to take 3-4 hours in the intestine and 6-48 hours in the colon.

In some embodiments, the peptide inhibitors of the invention are, for example, less degraded (ie, more degraded) over a period of time, eg, more than 10% or about 10% more than control peptides. % Less, more than 20% or about 20% less, more than 30% or about 30% less, 40 or about 40 less, or more than 50% or about 50% less decomposed. In some embodiments, degradation stability is determined by any suitable method known in the art. In some embodiments, the degradation is enzymatic degradation. For example, in certain embodiments, peptide inhibitors are less sensitive to degradation by trypsin, chymotrypsin or elastase. In some embodiments, as a suitable method known in the art for determining degradation stability, the entire method is incorporated herein by Hawe et al., J Pharm Sci, Vol. 101, No. 3, et al. 2012, the methods described on pages 895-913 are mentioned. In some embodiments, such methods are used to select strong peptide sequences with enhanced shelf life. In certain embodiments, the SIF or SGF assays described herein are used to determine the stability of the peptide.

In certain embodiments, the peptide inhibitors of the invention inhibit or reduce IL-23-mediated inflammation. In a related embodiment, the peptide inhibitors of the invention are IL of one or more cytokines, eg, by binding IL-23R on the cell surface and thus inhibiting the binding of IL-23 to cells. -23 Inhibits or reduces mediated secretion. In certain embodiments, the peptide inhibitors of the invention inhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3, Stat4, or Stat5. Methods for determining inhibition of cytokine secretion and signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling can be determined by measuring inhibition of phosphoStat3 levels in cell lysates, as described in the accompanying Examples, including Example 2. it can.

In certain embodiments, the peptide inhibitors of the invention inhibit or reduce IL-23-mediated inflammation. In a related embodiment, the peptide inhibitors of the invention are IL of one or more cytokines, eg, by binding IL-23R on the cell surface and thus inhibiting the binding of IL-23 to cells. -23 Inhibits or reduces mediated secretion. In certain embodiments, the peptide inhibitors of the invention inhibit or reduce IL-23-mediated activation of Jak2, Tyk2, Stat1, Stat3, Stat4, or Stat5. Methods for determining inhibition of cytokine secretion and signaling molecules are known in the art. For example, inhibition of IL-23 / IL-23R signaling can be determined by measuring inhibition of phosphoStat3 levels in cell lysates, as described in the accompanying Examples, including Example 2. it can.

In certain embodiments, the peptide inhibitor has increased redox stability as compared to the control peptide. Various assays that can be used to determine redox stability are known and are available in the art. Any of these can be used to determine the redox stability of the peptide inhibitors of the invention.

In certain embodiments, the present invention provides various peptide inhibitors that bind or associate with IL-23R in vitro or in vivo to disrupt or block the binding of IL-23 to IL-23R. In certain embodiments, the peptide inhibitor binds and / or inhibits human IL-23R. In certain embodiments, the peptide inhibitor binds to and / or inhibits both human IL-23R and rodent IL-23R. In certain embodiments, the peptide inhibitor binds to and / or inhibits both human IL-23R and rat IL-23R. In certain embodiments, peptide inhibitors are at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of rat IL-23R, as determined, for example, by the assays described herein. , Or at least 95%, and also binds to or inhibits human IL-23R. In certain embodiments, the peptide inhibitor preferentially binds to and / or inhibits human and / or rat IL-23R as compared to mouse IL-23R. In certain embodiments, the peptide inhibitor binds preferentially to rat IL-23R as compared to mouse IL-23R. In certain embodiments, the peptide inhibitor binds preferentially to human IL-23R as compared to mouse IL-23R. In certain embodiments, the binding of the peptide inhibitor to mouse IL-23R is less than 75%, less than 50%, 40% of the binding of the same peptide inhibitor to human IL-23R and / or rat IL-23R. Less than, less than 30%, less than 20%, or less than 10%. In certain embodiments of peptide inhibitors that preferentially bind to and / or inhibit human IL-23R and / or rat IL-23R as compared to mouse IL-23R, the peptide inhibitor is a mouse. It binds to regions of IL-23R that are disturbed by the presence of additional amino acids that are present in IL-23R but not in human IL-23R or rat IL-23. In one embodiment, the additional amino acids present in mouse IL-23R are within the region corresponding to approximately amino acid residues 315-approximately amino acid residues 340 of the mouse IL23R protein, eg, within the amino acid region NWQPWSSPFVHQTSQETGKR (SEQ ID NO: 1355) . (See, for example, FIG. 4). In certain embodiments, the peptide inhibitor binds to the region of human IL-23R from approximately amino acid 230 to approximately amino acid residue 370.

In certain embodiments, the peptide inhibitor exhibits GI-specific localization after oral administration. In certain embodiments, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of orally administered peptide inhibitors are localized to gastrointestinal organs and tissues. In certain embodiments, the plasma levels of the orally administered peptide inhibitor are less than 20%, less than 10%, less than 5%, and 2% of the levels of the peptide inhibitor found in the small intestinal mucosa, colonic mucosa, or proximal colon. Less than%, less than 1% or less than 0.5%.

The various peptide inhibitors of the present invention can be constructed with only natural amino acids. Alternatively, the peptide inhibitor may include non-natural amino acids, including but not limited to modified amino acids. In certain embodiments, the modified amino acid comprises a naturally occurring amino acid that has been chemically modified to include one group, multiple groups, or chemical moieties that are not naturally present in the amino acid. The peptide inhibitors of the present invention may further comprise one or more D-amino acids. In addition, the peptide inhibitors of the invention may include amino acid analogs.

In certain embodiments, the peptide inhibitors of the invention comprise one or more modified or unnatural amino acids. For example, in certain embodiments, the peptide inhibitors are Dab, Dap, Pen, Sarc, Cit, Cav, hLeu, 2-Nal, D-1-Nal, D-2-Nal, Phe (4-OMe). , ΒhTrp, α-MePhe, α-MeTyr, α-MeTrp, β-HPhe, Phe (4-CF ₃ ), 2-2-indan, 1-1-indan, cyclobutyl, β-hPhe, Gla, Phe (4) -NH ₂ ), hPhe, 1-Nal, Nle, homo amino acid, D-amino acid, 4,4'-biphenylalanine (Bip), cyclobutyl-Ala, hCha, βhPhe, βGlu, Phe (4-guanidino), Ph [ 4- (2-Aminoethoxy)], Phe [4- (2-Acetylaminoethoxy)], Phe (4-CONH ₂ ), Phe (4-Me), Tyr (Bzl), or Tyr (Me), Phe (3,4-diF ₂ ), Phe (3,4-Cl ₂ ), Phe (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)] , Ph (Br), Ph (4-CONH ₂ ), Ph (Cl), Ph (4-CN), Ph (4-Guazino), Ph (4-Me), Ph (4-NH ₂ ), Ph ( 4-N3), Tyr, Tyr (Bzl), or Tyr (Me), Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl ₂ ), Tyr (3-tBu), and Includes one or more of various N-methylated amino acids and alpha-methyl amino acids. In some embodiments of the invention, the peptide inhibitor comprises one or more unnatural amino acids shown in Table 1A. Other modified or unnatural amino acids, and various other substitutions of natural amino acids with modified or unnatural amino acids can be made to achieve similar desired results, and such substitutions can be made in the book. Those skilled in the art will appreciate that it falls within the scope of the teaching and gist of the invention. In certain embodiments, the peptide inhibitors of the invention are, but are not limited to, the amino acid sequences or peptide inhibitors shown in any one of the tables herein, the accompanying sequence listing or the accompanying figure. Includes any of those described herein, including any that comprises a structure in which one or more residues have been replaced with a modified or unnatural amino acid.

The present invention includes either free or salt forms of any of the peptide inhibitors described herein. Accordingly, multiple embodiments of any peptide inhibitor (and related uses thereof) described herein include a pharmaceutically acceptable salt of the peptide inhibitor.

The present invention is limited to, but is not limited to, any peptide inhibition described herein, including any one of the tables of the specification, including any of the attached sequence listings or the attached sequences shown in the illustration. Variants of the agent also include variants in which one or more L-amino acid residues are substituted with the D isomer form of the amino acid residue, eg, L-Ala is substituted with D-Ala.

In certain embodiments of the peptide inhibitors described herein, the peptide inhibitor comprises one or more unnatural or unnatural amino acid residues.

The present invention also includes any peptide monomer inhibitor described herein linked to a linker moiety that includes any of the specific linker moieties described herein. In certain embodiments, the linker is attached to an N-terminal or C-terminal amino acid, while in other embodiments, the linker is attached to an internal amino acid. In certain embodiments, the linker is attached to two internal amino acids, eg, the amino acids inside each of the two monomeric subunits that form a dimer. In some embodiments of the invention, the peptide inhibitor is attached to one or more of the indicated linker moieties.

The present invention is a peptide and a peptide dimer comprising a peptide having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the peptide sequences of the peptide inhibitors described herein. Also includes the body. In certain embodiments, the peptide inhibitors of the invention have been conjugated to a core peptide sequence and one or more N-terminal and / or C-terminal modifications (eg, Ac and NH ₂ ) and / or one or more. Includes a linker moiety and / or an extended half-life moiety. As used herein, a core peptide sequence is an amino acid sequence of a peptide in the absence of such modifications and conjugates. For example, peptide inhibitors: [Palm]-[IsoGlu]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib ]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1115) , the core peptide sequence is [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2. -Nal]-[Aib]-[Lys (Ac)]-NN (SEQ ID NO: 1115) .

In certain embodiments, the peptide inhibitors of the invention or the monomeric subunits of the peptide inhibitors are 7-35 amino acid residues, 8-35 amino acid residues, 9-35 amino acid residues. Group, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues, 7-20 8 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 10-20 amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues , 9-18 amino acid residues, or 10-18 amino acid residues, and optionally one or more additional non-amino acid moieties such as conjugated chemical moieties, eg, PEG or linker. Including, then becoming, or consisting of a part. In certain embodiments, the peptide inhibitors of the invention (or any of the same, including, but not limited to, those of any embodiment of formula X, formula I, formula II, formula III, formula IV, or formula V. The monomer subunit) is greater than 10 amino acids, greater than 12 amino acids, greater than 15 amino acids, greater than 20 amino acids, greater than 25 amino acids, greater than 30 amino acids or greater than 35 amino acids, for example 35-50 amino acids. In certain embodiments, the peptide inhibitor (or monomeric subunit thereof) is less than 50 amino acids, less than 35 amino acids, less than 30 amino acids, less than 25 amino acids, less than 20 amino acids, less than 15 amino acids, less than 12 amino acids, or Less than 10 amino acids. In certain embodiments, the monomer subunit of the peptide inhibitor (or peptide monomer inhibitor) is 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, 11 amino acid residues. , 12 amino acid residues, 13 amino acid residues, 14 amino acid residues, 15 amino acid residues, 16 amino acid residues, 17 amino acid residues, 18 amino acid residues, 19 amino acid residues, 20 amino acid residues, 21 amino acid residues. , 22 amino acid residues, 23 amino acid residues, 24 amino acid residues, 25 amino acid residues, 26 amino acid residues, 27 amino acid residues, 28 amino acid residues, 29 amino acid residues, 30 amino acid residues, 31 amino acid residues. , 32 amino acid residues, 33 amino acid residues, 34 amino acid residues, or 35 amino acid residues. In certain embodiments, the monomeric subunits of the peptide inhibitors of the invention are 1 to 10-18 amino acid residues, and optionally a conjugated chemical moiety, such as a PEG or linker moiety. Contains or consists of one or more additional non-amino acid moieties. In various embodiments, the monomeric subunit contains 7-35 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 10 ~ 20 amino acid residues, 8-18 amino acid residues, 8-19 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues Contains or consists of amino acid residues. In a particular embodiment of any of the various formulas described herein, X is an amino acid residue of 7-35, an amino acid residue of 8-35, an amino acid residue of 9-35, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues, 7-18 amino acid residues Contains or consists of amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues.

Certain exemplary peptide inhibitors described herein contain 12 or more amino acid residues. However, the present invention relates to peptide sequences described herein, including peptide inhibitors having 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 11 amino acid residues. Also included are peptide inhibitors containing either fragment. For example, the peptide inhibitors of the present invention contain or consist of X4 to X9, X4 to X10, X4 to X11, X4 to X12, X4 to X13, X4 to X14, X4 to X15, or X4 to X16. including. In certain embodiments, the invention includes, but is not limited to, any of the formulas described herein, including those set forth in either a sequence listing or a table provided herein. Also, it comprises a peptide inhibitor having any of the sequences described herein, and one or more of X10, X11, X12, X13, X14, X15, or X16 is absent. In certain embodiments, one or more of X13, X14, X15 or X16 is absent.

In certain embodiments of the invention, the peptide inhibitor, or region X thereof, is not present in the antibody. In certain embodiments, the peptide inhibitor, or region X thereof, is not present within the _VH or _{VL region of the antibody.}

In certain embodiments of the peptide inhibitors described herein, the peptide inhibitor comprises one or more unnatural or unnatural amino acid residues.

In certain embodiments, the peptide inhibitors of the invention are cyclized by cyclic amide bonds, disulfide bonds, or thioether bonds. In certain embodiments, the bond is an intramolecular bond between two amino acid residues within the peptide inhibitor or monomer subunit thereof.

Peptide Inhibitors The peptide inhibitors of the invention are described herein, including peptides having any of the amino acid sequences described herein, compounds containing any of the peptide sequences described herein. Includes compounds having any of the structures described, and dimers of any of such peptides and compounds. The peptide inhibitor of the present invention is a peptide having no bond between X4 and X9 and a peptide having a bond between X4 and X9, for example, before and after introducing a cross-linking bond between X4 and X9. Contains both peptides. An exemplary peptide of the invention comprises the amino acid sequence or structure described in any of the attached tables, examples, figures and sequence listings.

In certain embodiments, the present invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof, of formula (Xa):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Xa) (SEQ ID NO: 1354)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is any amino acid or chemical moiety capable of forming a bond with X9;
X5 is any amino acid;
X6 is any amino acid;
X7 is any amino acid;
X8 is any amino acid;
X9 is any amino acid or chemical moiety capable of forming a bond with X4;
X10 is any amino acid;
X11 is any amino acid;
X12 is any amino acid;
X13 is any amino acid;
X14 is any amino acid;
X15 is any amino acid;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains the amino acid sequence of

X4 and X9 include peptide inhibitors capable of forming bonds with each other. In certain embodiments, the bond is a disulfide bond, thioether bond, lactam bond, triazole ring, selenoether bond, diselenide bond, or olefin bond. In certain embodiments, the bond is a disulfide bond or a thioether bond. In certain embodiments, the peptide inhibitor is cyclized by the binding between X4 and X9. In certain embodiments, the peptide inhibitor inhibits the binding of interleukin 23 (IL-23) to the IL-23 receptor. In certain embodiments, if X4 is not an amino acid, then X1, X2, and X3 are absent. In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent. In certain embodiments, X3 is a D-amino acid or is absent. In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

In one embodiment of the peptide inhibitor of formula Xa,
X1 does not exist;
X2 does not exist;
X3 is or does not exist; Glu, D-Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln;
X4 is Cys, Abu or Pen;
X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr;
X6 is Asp or Thr;
X7 is Trp or 6-chloro-Trp;
X8 is Glu, Gln or Val;
X9 is Cys, Abu or Pen;
X10 is a 2-Nal, Phe analog, Tyr, or Tyr analog, and in certain embodiments, X10 is 2-Nal, Phe (3,4-diF ₂ ), Phe (3,4-Cl). ₂ ), Phe (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)], Phe (Br), Phe (4-CONH ₂ ), Phe ( Cl), Phe (4-CN), Phe (4-Guadino), Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N3), Tyr, Tyr (Bzl), or Tyr (Me). ) And;
X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl ₂ ), Trp or Tyr (3-tBu);
X12 is 3-Pal, Accc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal. , Cav, Cha, Cit, Cpa, D-Asn, Glu, His, hLeu, hArg, Lys, Leu, Octgly, Orn, Piperidine, Arg, Ser, Thr or THP;
X13 is Cit, Asp, Dab, Dap, Phe, His, Dap (Peg2-Ac), Dap (pyroglutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid). , Lys (IVA), Lys (Peg4-isoGlu-Palm), Lys (pyroglutaric acid), Lys-succinic acid, Asn, Orn, Gln, Arg, Thr or Val;
X14 is Asp, Dab (Ac), Dap (Ac), Ph, His, Lys (Ac), Met, Asn (isobutyl), Gln, Arg, Tyr or Asp (1,4-diaminobutane);
X15 is Ala, Beta Ala, Glu, Gly, Asn, Gln, Arg or Ser.
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent.

In certain embodiments, X3 is absent. In certain embodiments, X16, X17, X18, X19 and X20 are absent. In certain embodiments, X4 and X9 are Cys and X4 and X9 are linked by disulfide bonds. In certain embodiments, X4 is Abu, X9 is Pen, and X4 and X9 are linked by thioether bonds. In certain embodiments, X4 is Abu, X9 is Cys, and X4 and X9 are linked by a thioether bond.

In another embodiment of the peptide inhibitor of formula Xa,
X1 does not exist;
X2 does not exist;
X3 is or does not exist; Glu, D-Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln;
X4 is Cys, Abu or Pen;
X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr;
X6 is Asp or Thr;
X7 is Trp or 6-chloro-Trp;
X8 is Gln or Val;
X9 is Cys, Abu or Pen;
X10 is a 2-Nal, Phe analog, Tyr, or Tyr analog, and in certain embodiments, X10 is 2-Nal, Phe (3,4-diF ₂ ), Phe (3-Me), Ph [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)], Phe (Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN) ), Ph (4-Guazino), Ph (4-Me), Ph (4-NH ₂ ), Ph (4-N ₃ ), Tyr, Tyr (Bzl), or Tyr (Me);
X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl ₂ ), Trp or Tyr (3-tBu);
X12 is 3-Pal, Accc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal. , Cav, Cha, Cit, Cpa, D-Asn, His, hLeu, hArg, Lys, Leu, Octgly, Orn, 4-amino-4-carboxy-piperidine, or THP;
X13 is Cit, Asp, Dab, Dap, Phe, His, Dap (Peg2-Ac), Dap (pyroglutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid). , Lys (IVA), Lys (Peg4-isoGlu-Palm), Lys (pyroglutaric acid), Lys-succinic acid, Asn, Orn, Gln, Arg, Thr or Val;
X14 is Dab (Ac), Dap (Ac), Ph, His, Lys (Ac), Met, Asn, Gln, Arg, or Tyr;
X15 is Ala, βAla, Gly, Asn, Gln, or Ser.
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent.

In some embodiments, X3 is absent. In certain embodiments, X16, X17, X18, X19 and X20 are absent. In certain embodiments, X4 and X9 are Cys and X4 and X9 are linked by disulfide bonds. In certain embodiments, X4 is Abu, X9 is Pen, and X4 and X9 are linked by thioether bonds. In certain embodiments, X4 is Abu, X9 is Cys, and X4 and X9 are linked by a thioether bond.

In another embodiment of the peptide inhibitor of formula Xa,
X1 does not exist;
X2 does not exist;
X3 is or does not exist; Glu, D-Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln;
X4 is Cys, Abu or Pen;
X5 is Dap, Dap (Ac), Gly, Lys, Gln, Arg, Ser, Thr or Asn;
X6 is Thr;
X7 is Trp or 6-chloro-Trp;
X8 is Gln;
X9 is Cys, Abu or Pen;
X10 is a 2-Nal, Phe analog, Tyr, or Tyr analog, and in certain embodiments, X10 is 2-Nal, Phe (3-Me), Phe [4- (2-aminoethoxy). ], Phe [4- (2-acetylaminoethoxy)], Phe (4-CONH ₂ ), Phe (4-Me), Phe (4-NH ₂ ), Tyr, Tyr (Bzl), or Tyr (Me). Is;
X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), Phe (3,4-Cl ₂ ), or Trp;
X12 includes Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, hLeu. , Lys, Leu, Arg or THP;
X13 is Cit, Asp, Dap, Dap (Peg2-Ac), Dap (pyroglutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (Peg4-isoGlu-Palm), Lys (pyroglutaric acid), Lys (succinic acid), Asn, Orn, Gln, Arg, or Val;
X14 is Dab (Ac), Dap (Ac), His, Lys (Ac), Asn, Gln, or Tyr;
X15 is Ala, Beta Ala, Gly, Asn, Gln, or Ser.
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent.

In some embodiments, X3 is absent. In certain embodiments, X16, X17, X18, X19 and X20 are absent. In certain embodiments, X4 and X9 are Cys and X4 and X9 are linked by disulfide bonds. In certain embodiments, X4 is Abu, X9 is Pen, and X4 and X9 are linked by thioether bonds. In certain embodiments, X4 is Abu, X9 is Cys, and X4 and X9 are linked by a thioether bond.

In another embodiment of the peptide inhibitor of formula Xa,
X1 does not exist;
X2 does not exist;
X3 is or does not exist; Glu, D-Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln;
X4 is Cys, Abu or Pen;
X5 is Dap, Dap (Ac), Gln, Ser, Thr or Asn;
X6 is Thr;
X7 is Trp;
X8 is Gln;
X9 is Cys, Abu or Pen;
X10 is a Phe analog, Tyr, or Tyr analog, and in certain embodiments, X10 is Ph [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)], Ph (4-CONH ₂ ), Phe (4-Me), Tyr, Tyr (Bzl), or Tyr (Me);
X11 is 2-Nal or Trp;
X12 is Accc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, hLeu, Leu, or THP;
X13 is Cit, Asp, Glu, Lys, Lys (Ac), Asn, or Gln;
X14 is Dab (Ac), Asn, or His;
X15 is Ala, Beta Ala, Gly, Asn, or Gln;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent.

In some embodiments, X3 is absent. In certain embodiments, X16, X17, X18, X19 and X20 are absent. In certain embodiments, X4 and X9 are Cys and X4 and X9 are linked by disulfide bonds. In certain embodiments, X4 is Abu, X9 is Pen, and X4 and X9 are linked by thioether bonds. In certain embodiments, X4 is Abu, X9 is Cys, and X4 and X9 are linked by a thioether bond.

In certain embodiments, the peptide inhibitor comprises an amino acid sequence set forth in any of the various formulas described herein, eg, Ia-It, IIa-IId, IIIa-IIIe, or IV.

In certain embodiments, the present invention comprises a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof.

Here, this peptide inhibitor is expressed in formula I:
R ^1- X-R ² (I)
Has the structure of

In the formula, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, pegged alone or as a spacer of either of those described above. Including version;

R ² is bound, OH or NH ₂ ;

X is an amino acid sequence containing, for example, 7 to 35 amino acid residues. In certain embodiments, R ² is OH or NH ₂ .

In certain embodiments, X comprises a sequence of formula Xa.

In a particular embodiment of formula (I), X is the formula Ia :.
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ia) (SEQ ID NO: 1356)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu , Β-Azido-Ala-OH, propargylglycine, 2- (3'-butenyl) glycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, 2-( 5'-hexenyl) glycine, or absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, CitDap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Leu, Val, Phe, Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) ) Glycine, or 2- (5'-hexenyl) glycine;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4- Carboxy-tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal , Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, TyrβhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac), or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of.
In certain embodiments of Ia, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal or 2-Nal; X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala or t-butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala or Sar; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments of formula I, X is the formula Ib:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ib) (SEQ ID NO: 1357)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D. -Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu, β -Azido-Ala-OH, propargylglycine, 2- (3'-butenyl) glycine, 2-2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, 2-( 5'-hexenyl) glycine or absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, CitDap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, or 2- (5'- Hexenyl) glycine;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ), Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy. -Tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAlaAib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Grn;
X14 is Ph, Tyr, or βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of.

In certain embodiments of Ib, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal or 2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala or t-butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu , Lys, Val, βhAla or Aib; X14 is Ph, Tyr or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp, Glu, Ala, AEA. , AEP, βhAla, Gaba, or absent; X17 is Leu, Lys, Arg, or absent.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments of formula I, X is the formula Ic:
X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Ic) (SEQ ID NO: 1358)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu , Β-Azido-Ala-OH, propargylglycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, 2- (5'-hexenyl) glycine, Or does not exist;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, CitDap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, or 2- (5'- Hexenyl) glycine;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly; 4-amino-4-carboxy. -Tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, or Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. Yes;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of.

In certain embodiments of Ic, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib, or D-Sark; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Ph, Arg, N-Me-His, Val. , Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, Or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Grn, Ala, or Sarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or non-existent; X17 is Leu, Lys, Arg or non-existent.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments of formula I, X is the formula Id:
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Id) (SEQ ID NO: 1359)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, CitDap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X10 is Tyr Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (4). 2- (Acetyl-Aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanizino), Phe (4- Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ), Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy. -Tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His, Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally linked by intramolecular disulfide bridges.

In certain embodiments of Id, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe , Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe. , Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp. , Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments of formula I, X is the formula Ie:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Ie) (SEQ ID NO: 1360)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Pen, hCys, D-Pen, D-Cys, or D-hCys;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, CitDap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Pen, hCys, D-Pen, D-Cys, D-hCys;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy. -Tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally linked by intramolecular disulfide bridges.

In certain embodiments of Ie, the X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe , Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe. , Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp. , Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments, both X4 and X9 are Pens.

In certain embodiments of formula I, X is the formula If:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(If) (SEQ ID NO: 1361)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, or Asp;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-Me-Gln, N-Me-Arg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, or Asp;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly, 4-amino-4-. Carboxy-tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal , Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally cyclized by intramolecular binding.

In certain embodiments of If, X5 comprises Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, or D-Sark; X6 is Asp, Thr, Asn, The, D-Asp, D-Thr, D-Asn, or D-Phe; X8 Is Val, Gln, Glu, or Lys; X9 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, or Asp. X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit. , HLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, or Aib; , Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Grn, Ala, or Sar; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or is present. No; X17 is Leu, Lys, Arg, or is absent.

In certain embodiments, the intramolecular bond is a lactam bond.

In certain embodiments of formula I, X is the formula Ig:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20
(Ig) (SEQ ID NO: 1362)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is β-azido-Ala-OH, or propargylglycine;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is β-azido-Ala-OH or propargylglycine;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly, 4-amino-4-. Carboxy-tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal , Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally cyclized through the intramolecular triazole ring.

In certain embodiments of Ig, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib, or D-Sark; X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe; X8 is , Val, Gln, Glu, or Lys; X9 is β-azido-Ala-OH or propargylglycine; X10 is Tyr or Ph; X11 is Trp, 1-Nal, or 2-Nal. X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13. Are Thr, Sar, Glu, Ph, Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, Or Sarc; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or is absent; X17 is Leu, Lys, Arg or is absent.

In certain embodiments of formula I, X is the formula Ih:
X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20
(Ih) (SEQ ID NO: 1363)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, or 2- (5'-hexenyl) glycine;
X5 is Ala, Arg, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, or Asn;
X8 is Val, Gln, or Glu;
X9 is 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, or 2- (5'-hexenyl) glycine;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Grn. ;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally cyclized by intramolecular ring closing metathesis to produce the corresponding olefin.

In certain embodiments of Ih, X5 is Ala, Arg, or Sar; X6 is Asp, Thr, or Asn; X11 is Trp, 1-Nal, or 2-Nal; X13 is , Thr, Sar, Glu, Ph, Arg, Leu, Lys, βhAla, Val, or Aib; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp, Glu, Ala. , AEA, AEP, βhAla, Gaba, or absent; X17 is Leu, Lys, Arg, or absent.

In certain embodiments of formula I, X is the formula Ii:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ii) (SEQ ID NO: 1364)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-Chloro-butyric acid, or 3-chloro-isobutyric acid;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D. -Aib, or D-Sark, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, or Abu;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy. -Tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally cyclized by an intramolecular thioether bond.

In certain embodiments of Ii, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib, or D-Sark; X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, or D-Phe; X10 is , Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, or is absent; X17 is Leu, Lys, Arg, or is absent.

In certain embodiments of formula I, X is the formula Ij:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ij) (SEQ ID NO: 1365)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Sec, 2-chloromethylbenzoic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, or Abu;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Sec or Abu;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2-Aminoethoxy), Phe [4- (2- (Acetyl-Aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN) , Ph (4-guanizino), Ph (4-Me), Ph (4-NH ₂ ), Ph (4-N ₃ ), Ph (4-OMe), Ph (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino-4-carboxy. -Tetrahydropyran, Achc, Acpc, Acbc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of

X4 and X9 are optionally cyclized by an intramolecular thioseleno or diselenide bond.

In certain embodiments of Ij, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, βhAla, or Aib; X14 is Ph, Tyr, or βhPhe; X15 is Gly, Ser, Thr, Gln, Ala, or Sar; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments of formula I, X is the formula Ik:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ik) (SEQ ID NO: 1366)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, or does not exist;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, α -MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Leu, Val, Phe, or Ser;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Ph, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino -4-carboxy-tetrahydropyran, Accc, Acpc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. ;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains an array of.

In certain embodiments of Ik, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D. -Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Leu or absent; X17 is Leu, Lys, Arg Yes or no.
In certain embodiments of formula I, X is the formula Il:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Il) (SEQ ID NO: 1367)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, or does not exist;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, or Ph;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Leu, Val, Phe, or Ser;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Ph, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4-amino -4-carboxy-tetrahydropyran, Accc, Acpc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sar, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. Or does not exist;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array.

In certain embodiments of Il, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, or Sar; X10 is Tyr or Ph; X11 is Trp, 1-Nal, Or 2-Nal; X12 is His, Ph, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t -Butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Val, βhAla, Aib or absent; X14 is Ph, Tyr, βhPhe, Or does not exist; X15 is Gly, Ser, Thr, Gln, Ala, Sarc, or does not exist; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Leu, Or absent; X17 is Leu, Lys, Arg, or is absent.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, or Aib.

In certain embodiments, the X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp. In certain embodiments, X14 is Ph, Tyr, or βhPhe.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc.

In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Aib, α-MeGly (diethyl), α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments of peptide inhibitors of formula I, X is of formula Im :.
X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Im) (SEQ ID NO: 1368)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, or does not exist;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, or Gln;
X6 is Asp, Thr, Asn, or Ph;
X8 is Val, Gln, Glu, or Lys;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Leu, Val, Phe, or Ser;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ); 5-hydroxy-Trp, Phe (3,4-Cl ₂ ), or Tyr (3-t-Bu). ;
X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly, 4-amino-4-. Carboxy-tetrahydropyran, Acch, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal , Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sar, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. Or does not exist;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac), or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of.

In certain embodiments of Im, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, or Sar; X11 is Trp, 1-Nal, or 2-Nal; X12. Are His, Ph, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-Butyl-Ala, or t-Butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg Yes or no.

In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, or Aib. In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln.

In certain embodiments, the X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp. In certain embodiments, X14 is Ph, Tyr, or βhPhe.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala, or Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc.

In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Aib, α-MeGly (diethyl), α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14, and X15 are present.

In certain embodiments, X4 is present.

In certain embodiments, the peptide inhibitor is cyclized.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments, the peptide inhibitor is cyclized or contains an intramolecular bond between X4 and X9.

In certain embodiments of peptide inhibitors of formula I, X is of formula In:
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (In) (SEQ ID NO: 1369)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, or Ph;
X8 is Val, Gln, Glu, or Lys;
X10 is Tyr Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (4). 2- (Acetyl-Aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanizino), Phe (4- Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly, 4- Amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer , Α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
X13 is Thr, Sar, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. Or does not exist;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of

Cys at the X4 position and Cys at the X9 position are optionally linked by a disulfide bridge.

In certain embodiments of In, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly. , Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3- Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl) ), Phe (4-CN), Phe (4-guanidino), Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4- OBzl) or Tyr; X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3- t-Bu); X12 is His, Ph, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly. , 4-Amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib. , Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln, or absent; X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp, or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; and X17 is Leu, Lys, Arg or absent. do not.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, or Aib.

In certain embodiments, the X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp. In certain embodiments, X14 is Ph, Tyr, or βhPhe.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc.

In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of peptide inhibitors of formula I, X is the formula Io:
X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-X14-X15-X16-X17-X18-X19-X20 (Io) (SEQ ID NO: 1370)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, or Ph;
X8 is Val, Gln, Glu, or Lys;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X13 is Thr, Sar, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, or Gln. Or does not exist;
X14 is Ph, Tyr, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp, or is absent;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of

Cys at the X4 position and Cys at the X9 position are optionally linked by a disulfide bridge.

In certain embodiments of Io, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly. , Lys, Asn, N-MeGln, N-MeArg, Orn or Gln; X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe ( 3,4-Cl ₂ ) or Tyr (3-t-Bu); X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp , Dab, Dap, Glu, hArg, Lys, Asn, Orn, Gln, or absent; X14 is Ph, Tyr, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) Asp or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn, or absent; X16 is Asp, Glu, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla or Aib.

In certain embodiments, the X14 is Ph, Tyr, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp. In certain embodiments, X14 is Ph or Tyr.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of peptide inhibitors of formula I, X is the formula Ip:
X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20 (Ip) (SEQ ID NO: 1371)

(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is Ala, Arg, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, or Asn;
X8 is Val, Gln, or Glu;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
Is X13 Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Grn? , Or does not exist;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg Asn, or is absent;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of

Cys at the X4 position and Cys at the X9 position are optionally linked by a disulfide bridge.

In certain embodiments of Ip, X5 is Ala, Arg, or Sar; X11 is Trp, 1-Nal, or 2-Nal; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba or absent; X17 is Leu, Lys, Arg or absent.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla or Aib.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of peptide inhibitors of formula I, X is of formula Iq:
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Iq) (SEQ ID NO: 1372) ,
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D. -Aib, D-Sark, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln;
X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, or D-Phe;
X8 is Val, Gln, Glu, or Lys;
X10 is Tyr, Phe, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)], Phe [4- (2- (Acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino), Phe (4) -Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is His, Phe, Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, t-butyl-Gly, 4- Amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer , Α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys;
Is X13 Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Grn? , Or does not exist;
X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac), Asp, or is absent;
X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg, Asn, or is absent;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of

Cys at the X4 position and Cys at the X9 position are arbitrarily connected.

In certain embodiments of Iq, X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Phe , Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly, Ser, Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Leu or absent; X17 is Leu, Lys, Arg or does not exist.

In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla or Aib.

In certain embodiments, the X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac), or Asp. In certain embodiments, X14 is Ph, Tyr or βhPhe.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments, IQ is the formula Iq':
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15 (Iq') (SEQ ID NO: 1373)
(In the formula, X1 to X14 have the definitions provided for IQ)
Contains or consists of an array of
Cys at the X4 position and Cys at the X9 position are arbitrarily connected.

In certain embodiments of Iq', X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu. , D-Thr, D-Ser, D-Aib, or D-Sark; X10 is Tyr or Phe; X11 is Trp, 1-Nal, or 2-Nal; X12 is His, Ph, Arg, N-Me-His, Val, or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, or t-butyl-Gly; X13 is Thr. , Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Val, Aib or absent; X14 is Phe, Tyr, βhPhe or absent; X15 is Gly, Ser , Thr, Gln, Ala, Sarc or absent; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Leu or absent; X17 is Leu, Lys , Arg, or does not exist.

In certain embodiments, the X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn. , Or Gln. In certain embodiments, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla or Aib.

In certain embodiments, the X14 is Ph, Tyr, βhPhe, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp. In certain embodiments, X14 is Ph, Tyr or βhPhe.

In certain embodiments, the X15 is Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X14 is Ph, Tyr or βhPhe.

In certain embodiments, X13 is present.

In certain embodiments, X13 and X14 are present.

In certain embodiments, X13, X14 and X15 are present.

In certain embodiments of peptide inhibitors of formula I, X is the formula Ir:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ir)
(SEQ ID NO: 1374)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu. , D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu , Β-Azido-Ala-OH, propargylglycine, 2- (3'-butenyl) glycine, 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, 2-( 5'-hexenyl) glycine, Abu or absent;
X5 is any amino acid;
X6 is any amino acid;
X7 is the corresponding α-methyl amino acid type of Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly, or any of those mentioned above;
X8 is any amino acid;
X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys. , Asp, Leu, Val, Ph, or Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'- Pentenyl) glycine, Ala, hCys, Abu, Met, MeCys, (D) Tyr or 2- (5'-hexenyl) glycine;
X10 is Tyr, Phe (4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,). 4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH ₂ ), Phe (4-phenoxy), Thr, Tic, Tyr (3-tBu), Phe (4-tBu), Phe ( 4-CN), Phe (4-Br), Phe (4-NH ₂ ), Phe (4-F), Phe (3,5-F ₂ ), Phe (4-CH ₂ CO ₂ H), Phe ( Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), Bip, Cha, 4-Pyridylalanine, βhTyr, OctGly, Phe (4-N ₃ ), Phe (4-Br) , Ph [4- (2-aminoethoxy)] or Ph, Ph analog, Tyr analog, or the corresponding α-methyl amino acid type of any of those described above;
X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), Phe (4-CO ₂ H), βhPhe. (4-F), α-Me-Trp, 4 _{-Phenylcyclohexyl, Phe (4-CF 3} ), Phe (3,4-OMe ₂ ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5) -Phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7-tri-tert-butyl), Phe (4) -O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino, Phe (4-OBzl), Octgly, Glu (Bzl), 4-Phenylalanine, Phe [4- (4-(4) 2-Aminoethoxy)], 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norhalman, Phe (4-CONH ₂ ), Phe (3,4-dimethoxy) ), Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalaninealanine or Bip, or the corresponding α-methyl amino acid of any of the above. Is a mold;
X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, α-MeLys, D-Ala, (D) Asn. , (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, β-Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal, β-spiro -Pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle or t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys, or the corresponding α-methylamino acid type of any of those described above;
X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val, βhAla, Lys (Ac), (D) Asn, (D) Leu, (D) Phe, ( D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl , Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tle or Aib, or the corresponding α-methylamino acid type of any of the above;
X14 is Ph, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys (Ac), Dap (Ac), Asp, Pro, Gln, Arg, Ser, Thr, Tic or βhPhe, or as described above. One of the corresponding α-methylamino acid types;
X15 is Gly, Ser, Thr, Gln, Ala, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Aea, Asp, Asn, Glu. , Ph, Gly, Lys, Leu, Pro, Arg, β-Ala, or Sarc, or the corresponding α-methylamino acid type of any of those described above;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of.

In certain embodiments, the peptides are cyclized via X4 and X9.

In certain embodiments, X3 is Glu, D-Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu, (D) Gln.

In certain embodiments of Ir, X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), Phe. (4-CO ₂ H), βhPhe (4-F), α-Me-Trp, 4 _{-Phenylcyclohexyl, Phe (4-CF 3} ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5-) Phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7-tri-tert-butyl), Phe (4- Oallyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino, Phe (4-OBzl), Octgly, Glu (Bzl), 4-Phenylalanine, Phe [4- (2) -Aminoethoxy)], 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norhalman, Phe (4-CONH ₂ ), Phe (3,4-dimethoxy) , Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalaninealanine or Bip, or the corresponding α-methyl amino acid type of any of those described above. X12 is His, Phe, Arg, N-Me-His, or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, α-MeLys, D-Ala, ( D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, β-Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal, Correspondence to β-spiro-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Grn, Ser, Thr, Tle or t-butyl-Gly, or any of the above. X13 is the α-methyl amino acid type; Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Arg, Orn, Val, βhAla, Lys (Ac), (D) Asn, (D) Leu, ( D) Ph, (D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly , HLeu, Asn, Ogl, Pro, Gln, Ser, β-spiro-pip, Thr, Tba, Tle or Aib, or the corresponding α-methylamino acid type of any of those described above; X14 is Ph, Tyr. , Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or βhPhe, or the corresponding α-methylamino acid type of any of those described above; X15 is Gly. , Ser, Thr, Gln, Ala, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Thr, Aea, Asp, Asn, Glu, Ph, Gly , Lys, Leu, Pro, Arg or Sarc, or the corresponding α-methylamino acid type of any of those described above; X16 is Asp, Glu, Ala, AEA, AEP, βhAla, Gaba, Gly, Ser, Pro. , Asn, Thr, or absent, or the corresponding α-methylamino acid type of any of those described above; X17 is Leu, Lys, Arg, Glu, Ser, Gly, Gln or is present. No, or the corresponding α-methylamino acid type of any of those mentioned above.

In certain embodiments, both X4 and X9 are Pens. In certain embodiments, X4 and X9 are cyclized by disulfide bonds.

In certain embodiments, X4 is Abu and X9 is Cys. In certain embodiments, X4 and X9 are cyclized by thioether bonds.

In certain embodiments, the X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr. , D-Ser, D-Aib, Cys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-Asn, N-Me-Lys, N -Me-Gln, Orn, Pro, Pen, Gln, Val, αMe-Lys, αMe-Orn, or D-Sark, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys , Asn, N-MeGln, N-MeArg, or Gln. In certain embodiments, X5 is Gln or Asn. In certain embodiments, the X5 is Ala, Arg, Glu, Ph, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr. , D-Ser, D-Aib, Cys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-Asn, N-Me-Lys, N -Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val, αMe-Lys, αMe-Orn, or D-Sark. In certain embodiments, X5 is Gln.

In certain embodiments, X6 is Asp, Thr, Asn, Ph, D-Asp, D-Thr, D-Asn, Glu, Arg, Ser or D-Phe. In certain embodiments, X6 is Thr.

In certain embodiments, X7 is Trp.

In certain embodiments, X8 is Val, Gln, Glu, Ph, Asn, Pro, Arg, Thr, Trp or Lys. In certain embodiments, X8 is Gln.

In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments, X11 is a Trp analog.

In certain embodiments, X10 is a Ph analog. In certain embodiments, X10 is also referred to as Phe (4-OMe), Phe (4-CONH ₂ ), or Phe [4- (2-aminoethoxy)] (here, Phe [4-2ae)]. Will be). In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)] (also referred to herein as Phe [4-2ae)].

In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X11 is 2-Nal.

In certain embodiments, X12 comprises α-MeLys, 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys ( Ac), α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal. In certain embodiments, X12 is α-MeLys.

In certain embodiments, X13 is Glu or Lys (Ac). In certain embodiments, X13 is Glu.

In certain embodiments, X14 is Asn.

In certain embodiments, X15 is Gly or Asn. In certain embodiments, X15 is Gly.

In certain embodiments, one or more of X16, X17, X18, X19 and X20, two or more, three or more, or four or more are absent. In certain embodiments, X16, X17, X18, X19 and X20 are absent.

In certain embodiments of Ir, X4 and X9 are Cys, X7 is Trp, and X18 is [(D) Lys]. In certain embodiments of Ir, X4 and X9 are Cys, X7 is Trp, X10 is Tyr, and X18 is [(D) Lys]. In certain embodiments of Ir, X4 and X9 are Cys, X7 is Trp, X1, X2 and X3 are absent, X17 is absent, and X18 is [(D) Lys. ], And X19 and X20 do not exist. In certain embodiments of Ir, X4 and X9 are Cys, X7 and X11 are Trp, X10 is Tyr, and X18 is [(D) Lys. In certain embodiments, X1, X2, and X3 are absent; in certain embodiments, X17 is absent.

In certain embodiments of Ir, X4 and X9 are Pens and X12 is α-MeLys. In certain embodiments of Ir, X4 and X9 are Pens, X12 is α-MeLys, and X16, X17, X18, X19 and X20 are absent. In certain embodiments of Ir, X4 and X9 are Pens and X12s are α-MeLys, 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc, Acvc, Agp, Aib, α-diethyl. Gly, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, X16, X17, X18, X19 and X20 are absent, X7 is Trp. .. In certain embodiments of Ir, X4 and X9 are Pens, X12 is α-MeLys, X16, X17, X18, X19 and X20 are absent, and X7 is Trp. In certain embodiments of Ir, X4 and X9 are Pens, X7 is Trp, and X12 is α-MeLys. In certain embodiments, X1, X2, and X3 are absent. In certain embodiments, there is a disulfide bond between X4 and X9.

In certain embodiments of Ir, X4 is Abu, X9 is Cys, and X12 is 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc, Acvc, Agp, Aib, α-. Diethyl Gly, α-MeLys, or α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal. In certain embodiments of Ir, X4 is Abu, X9 is Cys, and X12 is α-MeLys. In certain embodiments of Ir, X4 is Abu, X9 is Cys, and X12 is α-MeLys, 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, or α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal, where X16, X17, X18, X19 and X20 ,not exist. In certain embodiments of Ir, X4 is Abu, X9 is Cys, X12 is α-MeLys, and X16, X17, X18, X19 and X20 are absent. In certain embodiments of Ir, X4 is Abu, X9 is Cys, and X12 is α-MeLys, 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc, Acvc, Agpp, Aib, α-diethyl Gly, α-MeLys, or α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal, where X16, X17, X18, X19 and X20 , Does not exist and X7 is Trp. In certain embodiments of Ir, X4 is Abu, X9 is Cys, X12 is α-MeLys, X16, X17, X18, X19 and X20 are absent, and X7 is Trp. Is. In certain embodiments of Ir, X4 is Abu, X9 is Cys, X7 is Trp, and X12 is α-MeLys. In certain embodiments, X1, X2, and X3 are absent. In certain embodiments, there is a thioether bond between X4 and X9.

In certain embodiments of peptide inhibitors of formula I, X is the formula Is:
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-G-X16-X17-X18-X19-X20 (Is) (SEQ ID NO: 1375)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is any amino acid;
X6 is any amino acid;
X8 is any amino acid;
X10 is Tyr, 1-Nal 2-Nal, Phe (3,4-F ₂ ), Phe (3,4-Cl ₂ ), F (3-Me), Phe [4- (2-aminoethoxy)]. , Phe [4- (2- (acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino) ), Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl) or Tyr;
X11 is Trp 1-Nal, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp, Phe (3,4-Cl ₂ ) or Tyr (3-t-Bu);
X12 is Arg, Lys, His, hArg, Cit, Orn, 1-Nal, D-Ala, D-Leu, D-Phe, D-Asn, D-Asp, ASP, Leu, βhLeu, Aib, βhAla, βhVal. , ΒhArg, hLeu, Dap, 4-amino-4-carboxy-tetrahydropyran, Achc Accc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu , Α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg, or Lys.
X13 is Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, βhLeu, βhAla, βhVal βGlu, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Lys. (Ac), or Gln;
X14 is Ph, Tic, Asn, Tyr, Asn, Arg, Qln, Lys (Ac), His; Dap (Ac), Dab (Ac) or Asp;
X16 is any amino acid;
X17 does not exist;
X18 is D-Lys;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of.

In certain embodiments of Is, X10 is Tyr, 1-Nal or 2-Nal; X11 is Trp or 1-Nal; X12 is Arg, Lys, His, hArg, Cit, Orn, 1 -Nal, D-Ala, D-Leu, D-Phe, D-Asn, D-Asp, Agp, Leu, βhLeu, Aib, βhAla, βhVal, βhArg, hLeu or Dap; X13 is Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, βhLeu, βhAla, βhVal or βGLu; X14 is Ph, Tic, Asn or Tyr; X16 is AEA, Ala or βAla.

In certain embodiments, the X5 is Glu, Arg, Ala, N-Me-Arg, N-Me-Ala, N-Me-Gln, Orn, N-Me-Asn, N-Me-Lys, Ser, Grn. , Orn, Asn or Dap. In certain embodiments, the X5 is Glu, Arg, Ala, N-Me-Arg, N-Me-Ala, N-Me-Gln, Orn, N-Me-Asn, N-Me-Lys, Ser, Asn. Or Dap.

In certain embodiments, X6 is Asp or Thr.

In certain embodiments, X8 is Gln or Val.

In certain embodiments, the Is peptide is cyclized by a disulfide bond between X4 and X9.

In certain embodiments of peptide inhibitors of formula I, X is the formula It:
X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (It) (SEQ ID NO: 1376)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X5 is any amino acid;
X6 is any amino acid;
X8 is any amino acid;
X10 is Tyr, 1-Nal, 2-Nal, Phe [4- (2-aminoethoxy)], Phe (4-CONH ₂ ), Phe (4-OMe);
X11 is Trp, 1-Nal, 2-Nal, Bip, Phe (3,4-OMe ₂ ), 5-hydroxy-Trp;
X12 is Arg, His, 3-Pal, Leu, Thr, Grn, Asn, Glu, Ile, Phe, Ser, Lys, hLeu, α-MeLeu, D-Leu, D-Asn, h-Leu, 4-amino. -4-carboxy-tetrahydropyran, Achc Accc, Accc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer or α -MeVal;
X13 are Thr, Glu, Tyr, Lys, Gln, Asn, Lys, Lys (Ac), Asp, Arg, Ala, Ser, Leu;
X14 is Ph, Tyr, Asn, Gly, Ser, Met, Arg, His, Lys, Leu or Gln;
X15 is Gly, Ser, Arg, Leu, Asp, Ala, β-Ala, Glu, Arg or Asn;
X16 is absent or any amino acid;
X17 is absent or any amino acid;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains or consists of an array of.

In certain embodiments of It, X10 is Tyr, 1-Nal or 2-Nal; X11 is Trp, 1-Nal, 2-Nal or Bip; X12 is Arg, His, 3- Pal, Leu, Thr, Gln, Asn, Glu, Ile, Ph, Ser, Lys, hLeu, α-MeLeu, D-Leu, D-Asn, or h-Leu; X13 is Thr, Glu, Tyr, Lys, Gln, Asn, Lys, Asp, Arg, Ala, Ser, Leu; X15 is Gly, Ser, Arg, Leu, Asp or Ala; X16 is absent or Asn, Glu, Phe , Ala, Gly, Pro, Asp, Gln, Ser, Thr, D-Glu or Lys; X17 is absent or is Pro, Arg, Glu, Asp, Ser, Gly or Gln.

In certain embodiments, X5 is Ser, Asp, Asn, Gln, Ala, Met, Arg, His or Gly. In certain embodiments, X5 is Ser, Asp, Gln, Ala, Met, Arg, His or Gly.

In certain embodiments, X6 is either Asp, Ser or Thr.

In certain embodiments, X8 is Gln, Glu or Thr.

In certain embodiments, the peptide of It is cyclized by a disulfide bond between X4 and X9.

In a further embodiment, the invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate thereof, of formula (Va) :.
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Va)
(SEQ ID NO: 1377)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any D-amino acid or is absent;
X4 is a chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, Ser, hSer or X9;
X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr;
X6 is Thr, Ser, Asp, Ile or any amino acid;
X7 is Trp, 6-chloro-Trp, 1-Nap or 2-Nap;
X8 is Glu, Gln, Asn, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), or Lys (N-ε-palmitoyle). ;
X9 is any amino acid or chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, or X4;
X10 is a 2-Nal, Phe analog, Tyr, or Tyr analog;
X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl ₂ ), Trp or Tyr (3-tBu);
X12 is Aib, 4-amino-4-carboxy-tetrahydropyran, any alpha-methyl amino acid, alpha-ethyl-amino acid, Achc, Acvc, Acbc, Accc, 4-amino-4-carboxy-piperidine, 3-Pal. , Agp, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, a-α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa, D-Asn, Glu , His, hLeu, hArg, Lys, Leu, Octgly, Orn, Piperidine, Arg, Ser, Thr or THP;
X13 is Lys (Ac), Gln, Cit, Glu, or any amino acid;
X14 is Asn, Gln, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyl-L-γ-glutamyl)), Lys (N-ε-palmitoyl), or any amino acid. Is;
X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib or Cit;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains the amino acid sequence of
X4 and X9 include peptide inhibitors capable of forming bonds with each other. In certain embodiments, the bond is an ether, disulfide bond or thioether bond. In certain embodiments, the peptide inhibitor is cyclized by a bond between X4 and X9.

In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent.

In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

In a particular embodiment of formula (Ia), X10 is 2-Nal, Phe (3,4-diF ₂ ), Phe (3,4-Cl ₂ ), Phe (3-Me), Phe [4- (4). 2-Aminoethoxy)], Phe [4- (2-Acetylaminoethoxy)], Phe (Br), Phe (4-CONH2), Phe (Cl), Phe (4-CN), Phe (4-Guadino) , Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Tyr, Tyr (Bzl), or Tyr (Me). In certain embodiments of formula (Ia), X10 is Ph (4-ZR), Phe (3-ZR), or Phe (2-ZR), with R = CH ₂ (CH ₂ ) _n Y and n = 1-25, Z = NH, O, CO, CONH, or CH ₂ , and Y = NH ₂ , CO ₂ H, OH, or CH ₃ .

In a further related embodiment, the invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate compound thereof, of formula (Vb):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Vb)
(SEQ ID NO: 1378)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is D-Arg, D-Phe, any D amino acid, or is absent;
X4 is a chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, or X9;
X5 is Gln, Asn, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), or Lys (N-ε-palmitoyle);
X6 is Thr, Ser, Asp, Ile or any amino acid;
X7 is Trp, 1-Nap or 2-Nap;
X8 is Gln, Asn, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), or Lys (N-ε-palmitoyle);
X9 is any amino acid or chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, X4;
X10 is Ph [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)], Phe (4-CONH ₂ ), Phe (4-Guadino), Phe (4-NH ₂ ). , Tyr (Me) or Phe (4-ZR), R = CH ₂ (CH ₂ ) _n Y; n = 1-25; Z = O, CO, NH, CONH, or CH ₂ ; and Y = NH ₂ , CO ₂ H, OH, or CH ₃ ;
X11 is 2-Nal or Trp;
X12 is Aib, 4-amino-4-carboxy-tetrahydropyran, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, acid, Achc, Acvc, Acbc, Acpc, or 4-amino-4-carboxy-piperidine;
X13 is Lys (Ac), Gln, Cit, Glu, or any amino acid;
X14 is Asn, Gln, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyl-L-γ-glutamyl)), Lys (N-ε-palmitoyl), or any amino acid. Is;
X15 is β-Ala, Asn, Gln, Ala, Ser, or Aib;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent)
Contains the amino acid sequence of
X4 and X9 include peptide inhibitors capable of forming bonds with each other. In certain embodiments, the bond is a disulfide bond or a thioether bond. In certain embodiments, the peptide inhibitor is cyclized by a bond between X4 and X9.

In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent.

In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

In another related embodiment, the invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate compound thereof, of formula (Vc):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Vc)
(SEQ ID NO: 1379)
(During the ceremony,
X1 does not exist;
X2 does not exist;
X3 is D-Arg or does not exist;
X4 is a chemical moiety capable of forming a bond with Cys, Pen, Abu, or X9;
X5 is Gln, Asn, Lys (Ac), Cit, or Cav;
X6 is Thr or Ser;
X7 is Trp, 1-Nap or 2-Nap;
X8 is Gln, Asn, Lys (Ac), Cit, or Cav;
X9 is any amino acid or chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, or X4;
X10 is Phe [4- (2-aminoethoxy)], Phe (4-CONH2) or Phe (4-OR), R = CH ₂ (CH ₂ ) _n Y; n = 1-25; and Y. = NH ₂ , CO ₂ H, OH, or CH ₃ ;
X11 is Trp or 2-Nal;
X12 is Aib, 4-amino-4-carboxy-tetrahydropyran, α-MeLys, α-MeLys (Ac), α-MeLeu, Acch, Acvc, Acbc or Accc;
X13 is Lys (Ac) or Glu;
X14 is Asn, Gln, Lys (Ac), Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), or Lys (N-ε-palmitoyle);
X15 is Gly, β-Ala, Asn, Gln, Ala, Ser, or Aib;
X16 does not exist;
X17 does not exist;
X18 does not exist;
X19 does not exist;
X20 does not exist)
Contains the amino acid sequence of
X4 and X9 include peptide inhibitors capable of forming bonds with each other. In certain embodiments, the bond is a disulfide bond or a thioether bond. In certain embodiments, the peptide inhibitor is cyclized by a bond between X4 and X9.

In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent.

In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

In another related embodiment, the invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate thereof, of formula (Vd):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Vd)
(SEQ ID NO: 1380)
(During the ceremony,
X1 does not exist;
X2 does not exist;
X3 does not exist;
X4 is Pen or Abu;
X5 is Gln or Asn;
X6 is Thr or Ser;
X7 is Trp;
X8 is Gln or Asn;
X9 is Pen or Cys;
X10 is Ph [4- (2-aminoethoxy)] or Phe (4-CONH ₂ );
X11 is Trp or 2-Nal;
X12 is Aib, 4-amino-4-carboxy-tetrahydropyran, α-MeLys, α-MeLeu, or Achc;
X13 is Lys (Ac) or Glu;
X14 is Asn, Gln or Lys (Ac);
X15 is Gly, Ala, Ser, β-Ala, Asn, or Gln;
X16 does not exist;
X17 does not exist;
X18 does not exist;
X19 does not exist;
X20 does not exist)
Contains the amino acid sequence of
X4 and X9 include peptide inhibitors capable of forming bonds with each other. In certain embodiments, the bond is a disulfide bond or a thioether bond. In certain embodiments, the peptide inhibitor is cyclized by a bond between X4 and X9.

Any of the peptide inhibitors of the invention (eg, any of the peptide inhibitors of formula I (eg, Ix, Ia-It)) can be further defined, for example, as described herein. It is understood that each of the further defined features can be applied to any peptide inhibitor that allows the presence of further defined features by the amino acids indicated at specific positions.

In certain embodiments, any of the Ph [4- (2-aminoethoxy)] residues present in the peptide inhibitor may be replaced with Ph [4- (2-acetylaminoethoxy)]. ..

In certain embodiments, X1 to X20 are shown at corresponding positions compared to the cyclized Pen-Pen or cyclized Abu-Cys residues of the exemplary peptide inhibitors listed in Tables 2-5. It is one of the amino acids.

In certain embodiments, but not limited to, those of formula (X), (Va), (Vb), Vc), (Vd), (Ve), (Vf), (Vg) or (Vh). Any of the peptide inhibitors described herein, including, further comprises a linker or spacer moiety between any two amino acid residues of the peptide. In certain embodiments, the linker or spacer moiety is a PEG moiety.

In certain embodiments, the peptide inhibitor is cyclized by a disulfide bridge.

In certain embodiments, X10 is Tyr, Phe [4- (2-aminoethoxy)], Phe (4-CONH ₂ ) or Phe (4-OMe). In certain embodiments, X10 is Tyr.

In certain embodiments, X11 is 2-Nal, Trp, or 5-hydroxy-Trp. In certain embodiments, X11 is Trp.

In certain embodiments, X10 is Tyr or Phe [4- (2-aminoethoxy)] and X11 is Trp or 2-Nal. In certain embodiments, X10 is Tyr and X11 is Trp.

In certain embodiments, X4 and X9 are both Cys.

In certain embodiments, X4 is Cys, Pen, hCys, or is absent.

In certain embodiments, both X7 and X11 are not necessarily W.

In certain embodiments, X7 and X11 are both W.

In certain embodiments, X7 and X11 are both W, X10 is Y, and X4 and X9 are both Cys.

In certain embodiments, X15 is Gly, Asn, β-ala or Ser. In certain embodiments, X15 is Gly or Ser.

In certain embodiments, X16 is AEA or AEP.

In certain embodiments, X10 is Tyr, Phe or Phe [4- (2-aminoethoxy). In certain embodiments, X10 is Tyr or Ph.

In certain embodiments, X11 is Trp or 2-Nal. In certain embodiments, X11 is Trp.

In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments, X18, X19 and X20 are absent.

In certain embodiments, X1, X2, X3, X18, X19 and X20 are absent.

In certain embodiments, one or more of X1, X2 or X3 is present.

In any particular embodiment of Ix, Ia to Ir, one of X1, X2 and X3 is present and the other two are absent. In one embodiment, the existing X1, X2 or X3 is Ala.

In certain embodiments, X3 is present. In certain embodiments, X3 is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln. In certain embodiments, X3 is (D) Arg or (D) Ph. In certain embodiments, X1 and X2 are absent and X3 is present.

In certain embodiments, two of X1, X2 and X3 are present and the other one is absent. In certain embodiments, the two present consist of SG, NK, DA, PE, QV or DR.

In certain embodiments, X1, X2 and X3 are present. In certain embodiments, X1, X2 and X3 consist of ADQ, KEN, VQE, GEE, DGF, NAD, ERN, RVG, KAN, or YED.

In certain embodiments, the peptide comprises an AEP residue. In certain embodiments, any of X15, X16, X17, X18, X19 or X20 is AEP.

In certain embodiments of either the peptide inhibitor or the peptide monomer subunit, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, Lys (Ac), βhAla, or Aib. In certain embodiments of either the peptide inhibitor or the peptide monomer subunit, X13 is Thr, Sarc, Glu, Ph, Arg, Leu, Lys, βhAla, or Aib. In certain embodiments, X14 is Ph, Asn, Tyr, or βhPhe. In certain embodiments, X14 is Ph, Tyr, or βhPhe. In certain embodiments, the X15 is Gly, Asn, Ser, Thr, Gln, Ala, or Sarc. In certain embodiments, X15 is Gly, Ser, Thr, Gln, Ala, or Sarc. In certain embodiments, X12 contains alpha amino acids such as 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac). ), Α-Me-Leu, α-MeOrn, α-MeSer, or α-MeVal.

In certain embodiments, X13 is present.

In certain embodiments, X13 and 14 are present.

In certain embodiments, X13, X14 and X15 are present.

In any one particular embodiment of Ia-It, one or more of X16-X20 are present. In certain embodiments, there are two or more or three or more of X16 to X20. In certain embodiments, X18 is [(D) Lys]. In certain embodiments, X17 is absent and X18 is [(D) Lys]. In certain embodiments where X4 and X9 are optionally Cys, X4 and X9 are Cys, X7 is Trp, and X18 is [(D) Lys]. In certain embodiments where X4 and X9 are optionally Cys, X4 and X9 are Cys, X7 is Trp, and X10 is Tyr or Ph [4- (2-aminoethoxy)]. , X18 is [(D) Lys]. In certain embodiments where X4 and X9 are optionally Cys, X4 and X9 are Cys, X7 is Trp, X10 is Tyr, and X18 is [(D) Lys]. .. In certain embodiments where X4 and X9 are optionally Cys, X4 and X9 are Cys, X7 is Trp, X1, X2 and X3 are absent, X17 is absent, and X18 is [(D) Lys] and X19 and X20 are absent. In certain embodiments of Ir, X4 and X9 are Cys, X7 and X11 are Trp, X10 is Tyr, and X18 is [(D) Lys. In certain embodiments, X1, X2, and X3 are absent; in certain embodiments, X17 is absent.

In certain embodiments, any of the peptide inhibitors (or monomeric subunits) described herein are cyclized. In certain embodiments, the peptide inhibitor is cyclized by a bond between two or more internal amino acids of the peptide inhibitor. In certain embodiments, the cyclized peptide inhibitor is not cyclized by the binding between the N-terminal and C-terminal amino acids of the peptide inhibitor. In certain embodiments, one of the amino acid residues involved in the intramolecular binding causes the peptide to be cyclized at the amino-terminal amino acid residue. In certain embodiments, any of the peptide inhibitors is cyclized by a peptide bond between its N-terminal amino acid and its C-terminal amino acid.

In certain embodiments of either the peptide inhibitor, or one or both of its monomeric subunits, the peptide inhibitor (or one or both of its monomeric subunits) is between X4 and X9. Is cyclized by an intramolecular bond or by a triazole ring. In certain embodiments, the intramolecular bond is either a disulfide bond, a thioether bond, a lactam bond, a triazole, a selenoether bond, a diselendide bond, or an olefin bond.

In one embodiment, the X4 and X9 of the peptide inhibitor (or one or both of its monomeric subunits) are Cys, Pen, hCys, D-Pen, D-Cys or D-hCys, which are intramolecular bonds. Is a disulfide bond. In certain embodiments, X4 and X9 are both Cys, or both X4 and X9 are Pens and the intramolecular bond is a disulfide bond.

In one embodiment, the peptide inhibitors (or one or both of their monomeric subunits) X4 and X9 are Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp. , D-Glu or D-Lys, and the intramolecular bond is a lactam bond.

In one embodiment, X4 is Abu, 2-chloromethylbenzoic acid, mercapto-butyric acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, or 3-chloro-. Isobutyric acid; X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys or D-hCys; the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu, X9 is Pen, and the intramolecular bond is a thioether bond. In certain embodiments, X4 is a 2-methylbenzoyl moiety capable of forming a thioether bond with X9, where X9 is Cys, N-Me-Cys, D-Cys, hCys, Pen, and D-. Selected from Pen. In certain embodiments, X4 is Abu, X9 is Cys, and the intramolecular bond is a thioether bond. In certain examples, in a peptide monomer, dimer, or subunit of any of the formulas and peptides described herein, X4 is a modified Ser, a modified hSer (eg, homo-Ser-Cl). ), The appropriate isostar, and the corresponding D-amino acid. In other cases, X4 is an aliphatic acid that has 1 to 4 carbons and forms a thioether bond with X9. In some cases, X4 is a 5- or 6-membered alicyclic acid with a modified 2-methyl group that forms a thioether bond with X9. In some embodiments, X4 is a 2-methylbenzoyl moiety. In certain embodiments, X4 is selected from Cys, hCys, Pen, and 2-methylbenzoyl moieties. In certain embodiments, X4 is selected from the group consisting of modified Ser, modified hSer, suitable isostars, and corresponding D-amino acids. In one embodiment, X4 is hSerCl (before a thioether bond is formed with X9 and thereby Cl is removed) or hSer precursor (eg, homo Ser (O-TBDMS); in other cases, X4. Is an aliphatic acid having 1 to 4 carbons and forming a thioether bond with X9. In some cases, X4 has a modified 2-methyl group forming a thioether bond with X9 5 A member or 6-membered alicyclic acid. In some cases, X4 is a 2-methylbenzoyl moiety. A particular practice in which X4 is not an amino acid but a chemical moiety that binds to X9. In form, X1, X2, and X3 are absent and X4 is conjugated or bound to X5. In some embodiments, the amino acid that is directly carboxyl side to X9 is an aromatic amino acid. In certain embodiments, X4 is an amino acid, and in other embodiments, X4 is another chemical moiety capable of binding to X9, eg, forming a thioether bond. In certain embodiments, X4 is another chemical moiety selected from any of the non-amino acid moieties described herein with respect to X4. Specific embodiments in which X4 is another chemical moiety. In certain embodiments, X1, X2 and X3 are absent and another chemical moiety is bound or conjugated to X5. In certain embodiments, X4 is, for example, 2-chloromethylbenzoic acid, 2 -Defined as a chemical moiety containing groups such as chlorides in chloro-acetic acid, 3-chloropropanoic acid, 4-chlorobutyric acid, 3-chloroisobutyric acid, but once the peptide undergoes ring closure cyclization to X4 and X9. Once a thioether bond is formed between, it will be understood by those skilled in the art that the chloride group is no longer present. Therefore, the description of the chemical moiety in X4 containing a reactive group such as chloride has chloride. It means both a group and a chloride-free group, i.e. after bond formation with X9. The present invention is set forth in any of the other formulas or tables described herein. Also includes peptides that contain the same structure as the one provided, but in which the thioether bond is reverse orientation. In such embodiments of the invention, amino acid residues or other chemicals generally shown in X4. The target portion is instead present at X9 and the amino acid residue shown at X9 is instead present at X4, i.e. the resulting thioae. It can be considered that the sulfur-containing amino acid residue of the tel bond is present in X4 instead of X9, and the amino acid residue or other moiety having a carbon side chain capable of forming a thioether bond with X4 is located in X9. it can. However, in this reverse orientation, the amino acid or chemical moiety at position X9 contains a free amine. For example, in certain embodiments, the amino acid of X9 is protected homoserine, such as homoserine (OTBDMS). Thus, in a particular reverse orientation embodiment of any peptide inhibitor of the formula described herein, X9 has one or two carbons and has a side chain that forms a thioether bond with X4. It is an amino acid residue having, and X4 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, and D-Pen. Specific examples of amino acid residues and other chemical moieties present at the corresponding positions in other formulas and tables are described herein.

Those skilled in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, the side chain of an amino acid can be modified when forming an intramolecular crosslink with the side chain of another amino acid, eg, one or more hydrogens can be removed or replaced by a bond. Furthermore, when hSer-Cl binds to an amino acid such as Cys or Pen by a thioether bond, the Cl moiety is released. Thus, as used herein, references to amino acids present in the peptide dimers of the invention (eg, at positions X4 or X9) or modified amino acids such as hSer-Cl are present within the peptides. It shall include both pre- and post-formation of such amino acids or modified amino acids forming intramolecular bonds.

In certain embodiments, the peptide inhibitor of the peptide inhibitor (or one or both of its monomeric subunits) is cyclized through a triazole ring. In certain embodiments, the peptide inhibitor of the peptide inhibitor (or one or both of its monomeric subunits) is linear or non-cyclized. In certain embodiments of any of the peptide inhibitors described herein, including both monomeric peptide inhibitors and dimeric peptide inhibitors, one (or) of the peptide monomer subunits. Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Iq', Ir, Is or It, IIa Contains or consists of a cyclized peptide having the structure or sequence described in any of ~ IId, IIIa ~ IIIe, Iva, or IVb.

In certain embodiments of either the peptide inhibitor or the monomeric subunit, X7 and X11 are both W.

In certain embodiments of either the peptide inhibitor or the monomeric subunit, both X7 and X11 are not necessarily W. In certain embodiments, X7 is W and X11 is not W.

In certain embodiments of either peptide inhibitors or monomeric subunits, X4 and X9 are thioether bonds, lactam bonds, triazoles, selenoethers, diselenide bonds, or olefin bonds with each other. It is an amino acid residue capable of forming an intramolecular bond.

In certain embodiments, X7 and X11 are both W, X10 is Y, Phe [4- (2-aminoethoxy) or Phe (CONH ₂ ), and X4 and X9 are relative to each other. It is an amino acid residue capable of forming an intramolecular bond, which is a thioether bond, a lactam bond, a triazole, a selenoether, a diselenide bond, or an olefin bond. In certain embodiments, X7 and X11 are both W, X10 is Y, and X4 and X9 are thioether-bonded, lactam-bonded, triazole, selenoether, diselenide-bonded, with each other. Alternatively, it is an amino acid residue capable of forming an intramolecular bond that is an olefin bond.

In certain embodiments, X7 and X11 are both W, X10 is Y, and X4 and X9 are both C.

In certain embodiments, X4 and X9 are Cys, Pen, hCys, D-Pen, D-Cys or D-hCys, respectively, and the intramolecular bond is a disulfide bond.

In certain embodiments, X4 and X9 are Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu or D-Lys, respectively, and are intramolecularly bound. Is a lactam bond.

In certain embodiments, X4 and X9 are β-azido-Ala-OH or propargylglycine, respectively, and the peptide inhibitor (or monomeric subunit) is cyclized through the triazole ring.

In certain embodiments, X4 and X9 are 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl) glycine, or 2- (5'-hexenyl) glycine, respectively. ), And the peptide inhibitor (or monomeric subunit) is cyclized by ring-closing metathesis to produce the corresponding olefin / "stapled peptide".

In certain embodiments, X4 is 2-chloromethylbenzoic acid, mercapto-butyric acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-iso. Butyric acid, or hSer (Cl); X9 is hSer (Cl), Cys, Pen, hCys, D-Pen, D-Cys or D-hCys; the intramolecular bond is a thioether bond. In certain embodiments, X4 is 2-chloromethylbenzoic acid or hSer (Cl); X9 is Cys or Pen and the intramolecular bond is a thioether bond. In certain embodiments, X4 is Abu and X9 is Cys or Pen.

In certain embodiments, X4 is 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, Abu or Sec; X9. Is Abu or Sec; the intramolecular bond is a selenoether bond.

In certain embodiments, the intramolecular bond between X4 and X9 is a diselenide bond.

In certain embodiments of any of the peptide inhibitors described herein, which contain two amino acid residues linked by an intramolecular bond, eg, a disulfide bond, eg, a cysteine residue, are involved in the intramolecular bond. Both of the two amino acid residues are not necessarily located at either the N-terminal or C-terminal positions of the peptide inhibitor. In certain embodiments, neither of the two amino acid residues involved in the intramolecular binding, such as cysteine, is located at the N-terminal or C-terminal of the peptide inhibitor. In other words, in certain embodiments, at least one or both of the two amino acid residues involved in the intramolecular binding, such as cysteine, are the amino acid residues inside the peptide inhibitor. In certain embodiments, neither of the two amino acid residues involved in the intramolecular binding, such as cysteine, is located at the C-terminal position of the peptide inhibitor. In certain embodiments, the two amino acid residues involved in the intramolecular binding are Cys, Pen, hCys, D-Pen, D-Cys or D-hCys residues. In certain embodiments, the two amino acid residues involved in the intramolecular bond are located at X4 and X9. In one embodiment, at X4 and X9, there is a disulfide bond between amino acid residues, such as cysteine or Pen residues. In certain embodiments, both X4 and X9 are Pens. In certain embodiments, one or both of the peptide monomer subunits in the peptide inhibitor are cyclized, for example, via a disulfide bond between the two Pen residues at positions X4 and X9. ..

In any particular embodiment of the peptide inhibitors described herein, the peptide monomer present in the peptide inhibitor, whether the peptide inhibitor is a monomer or a dimer. One or both of the subunits are cyclic or cyclized by an intramolecular bond such as a disulfide bond between two cysteine residues present in the peptide monomer or peptide monomer subunit. In certain embodiments, the peptide inhibitor comprises two or more cysteine residues. In some embodiments, the peptide inhibitor is cyclized by an intramolecular disulfide bond between the two cysteine residues. In certain embodiments of peptide inhibitors having any of the formulas described herein, the two cysteines are at positions X4 and X9. In other embodiments, one or both of the peptide monomer subunits of the peptide inhibitor are cyclized, for example, at positions X4 and X9 by disulfide bonds between the two Pen residues.

In some embodiments, the peptide inhibitor has a structure of any of the formulas described herein (eg, Formula I) and comprises a disulfide bond, such as an intramolecular disulfide bond or a thioether bond. Examples of such peptide inhibitors are shown in Tables 3A-3H and 4A, 4B, 9, 11 or 15. Such disulfide-bonded peptides may have certain advantages in that disulfide bonds enhance structural stability and can improve the biological activity of many bioactive peptides. However, in certain circumstances, these bonds are unstable to the reducing agent. Those skilled in the art will appreciate that simple isostar replacements can be applied to disulfides. Examples of such replacements include, but are not limited to, thioethers, dithioethers, serenoethers, diselenides, triazoles, lactams, alkanes and alkene groups. Thus, in certain embodiments of any of the peptide inhibitors described herein, one, two or more cysteine residues are shown below, but not limited to, for example, or the present. Substitute with a thioether, dithioether, selenoether, diselenide, triazole, lactam, alkane or alkene group, including any of those described herein. In certain embodiments, two of these substituted groups form a bond (eg, an intramolecular bond), thus cyclizing one or both of the peptide inhibitor or its monomer subunit.

In certain embodiments, the peptide inhibitors of the invention are described herein, for example, in Tables 3A-3H, 4A, 4B, 5A-5C, 6,7,8,9,10,11,12,13. , 14 or 15, which comprises or consists of the amino acid sequence shown in any one. In certain embodiments, the peptide inhibitors of the invention are described herein, for example, in Tables 3A-3H, 4A, 4B, 5A-5C, 6,7,8,9,10,11,12,13. , 14 or 15 has the structure shown in any one of.

In certain embodiments, the present invention describes the following (shown in the direction from N-terminus to C-terminus):
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₂ W (SEQ ID NO: 1381) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₂ (1-Nal) (SEQ ID NO: 1382) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₂ (2-Nal) (SEQ ID NO: 1383) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ YW (SEQ ID NO: 1384) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ Y (1-Nal) (SEQ ID NO: 1385) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ Y (2-Nal) (SEQ ID NO: 1386) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₂ X ₂ (SEQ ID NO: 1387) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₂ X ₂ X ₂ X ₂ X ₂ -[(D) Lys] (SEQ ID NO: 1388) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₃ X ₂ (SEQ ID NO: 1389) ;
X ₁ X ₂ X ₂ WX ₂ X ₁ X ₃ (1-Nal) (SEQ ID NO: 1390) ; and X ₁ X ₂ X ₂ WX ₂ X ₁ X ₃ (2-Nal) (SEQ ID NO: 1391)

(In the formula, W is tryptophan, Y is tyrosine, and each of the two X1 residues is an amino acid or other chemical moiety capable of forming an intramolecular bond with each other; X2 is. , Each independently selected from all amino acids, including, for example, natural amino acids, L-amino acids, D-amino acids, unnatural amino acids, and unnatural amino acids; X3 is any amino acid).
Includes a peptide inhibitor containing a core consensus sequence selected from one of the following. In certain embodiments, X3 is a Ph, Ph analog (eg, Ph [4- (2-aminoethoxy)] or Ph (4-CONH ₂ )), Tyr, or Tyr analog (eg, Tyr (Me)). )). In certain embodiments, X1 is selected from Cys, Pen and Abu, respectively. In certain embodiments, each X1 is Cys. In certain embodiments, each X1 is a Pen. In certain embodiments, one X1 is Cys and the other X1 is Abu. In certain embodiments, the N-terminal X1 is Abu and the C-terminal X1 is Cys. In certain embodiments, the N-terminal X1 is Cys and the C-terminal X1 is Abu. In certain embodiments, the residues between the two X1 residues are Gln, Thr, Trp and Gln. In certain embodiments, X1 is selected from Cys, Pen and Abu, respectively; X3 is Ph, Phe analog (eg, Ph [4- (2-aminoethoxy)] or Phe (4-carbamide). ), Tyr, or Tyr analog (eg, Tyr (Me)). In certain embodiments, X3 is a Ph analog.

In certain embodiments, the peptide inhibitors of the invention comprise any of the following consensus sequences in the formulas: X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14 and X15 are defined as shown in any of the various formulas or peptide inhibitors described herein:
X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 1392) ;
Pen-X5-X6-W-Q-Pen (SEQ ID NO: 1393) ;
Pen-X5-X6-W-X8-Pen (SEQ ID NO: 1394) ;
Pen-X5-X6-W-X8-Pen- [Phe (4-CONH2)] (SEQ ID NO: 1395) ;
Pen-X5-X6-W-X8-Pen- [Phe [4- (2-aminoethoxy)]] (SEQ ID NO: 1396) ;
X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 1397) ;
Abu-X5-X6-WQC (SEQ ID NO: 1398) ;
Abu-X5-X6-W-X8-C (SEQ ID NO: 1399) ;
Abu-X5-X6-W-X8-C- [Phe (4-CONH2)] (SEQ ID NO: 1400) ; or Abu-X5-X6-W-X8-C- [Phe [4- (2-aminoethoxy)] ]] (SEQ ID NO: 1401) .

In certain embodiments of either the peptide inhibitor or the monomeric subunit, X7 and X11 are both W. In certain embodiments of any of the peptide inhibitors, X7 and X11 are both W and X10 is Y. In certain embodiments, X7 and X11 are both W and X10 is Phe [4- (2-aminoethoxy)] or Phe (4-OMe).

In certain embodiments of either the peptide inhibitor or the monomeric subunit, both X7 and X11 are not necessarily W.

In certain embodiments of peptide inhibitors of formula I, X4 and X9 are Pen, respectively, and the intramolecular bond is a disulfide bond.

In certain embodiments, the peptide inhibitors of the invention comprise or consist of the amino acid sequences shown in any one of the tables, sequences or attachments herein.

In certain embodiments of any of the peptide inhibitors described herein that contain two amino acid residues linked by an intramolecular bond, eg, a disulfide bond, eg, a Pen residue, they are involved in the intramolecular bond. One or both of the two amino acid residues is not located at either the N-terminal or C-terminal position of the peptide inhibitor. In certain embodiments, neither of the two amino acid residues involved in the intramolecular binding, such as Pen, is located at the N-terminal or C-terminal of the peptide inhibitor. In other words, in certain embodiments, at least one or both of the two amino acid residues involved in the intramolecular binding, such as Pen, are the amino acid residues inside the peptide inhibitor. In certain embodiments, neither of the two amino acid residues involved in the intramolecular binding, such as Pen, is located at the C-terminal position of the peptide inhibitor.

In some embodiments in which the peptides of the invention are conjugated to acidic compounds such as isovaleric acid, isobutyric acid, valeric acid, the presence of such conjugations is referred to in the form of acids. Thus, but not limited to any form, for example, the conjugation of isovaleric acid with the peptide may be isovaleryl (eg, isovaleryl- [Pen] -QTWQ [Pen]-[Phe (4-OMe)). ]-[2-Nal]-[a-MeLys]-[Lys (Ac)]-NG-NH ₂ (SEQ ID NO: 262). Isovaleryl- [Pen] -QTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[a-MeLys]-[Lys (Ac)]-NG-NH _It is referred to as 2 (SEQ ID NO: 262).

The present invention further comprises a peptide inhibitor that selectively binds to an epitope or binding domain present in amino acid residues 230-349 of the human IL23R protein. In certain embodiments, the peptide inhibitor binds to human IL23R and not to mouse IL-23R. In certain embodiments, the peptide inhibitor also binds to rat IL-23R.

In certain embodiments of peptide inhibitors of formula I, X4 is Abu; X9 is Cys, Pen, homocys and the intramolecular bond is a thioether bond.

In certain embodiments, the peptide inhibitor does not include the compounds disclosed in PCT application No. PCT / US2014 / 03352 or PCT application No. PCT / US2015 / 0383370.

An exemplary peptide inhibitor containing a Pen-Pen disulfide bond

In certain embodiments, the present invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof, of formula II:
R ^1- X-R ² (II)
(In the formula, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alkyl sulfonate, acid, γ added to the N-terminus. -Glu or pGlu, including a pegged version (eg, 200 Da-60,000 Da) as a spacer, either alone or as described above;

R ² is bound, OH or NH ₂ ;

X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 amino acids)
Contains a peptide inhibitor having the structure of.

In certain embodiments of the peptide inhibitor of formula II, X is the formula IIa:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (IIa)
(SEQ ID NO: 1402)
(During the ceremony,
X1 is absent or any amino acid;
X2 is absent or any amino acid;
X3 is absent or any amino acid;
X4 is Pen, Cys or Homo Cys;
X5 is any amino acid;
X6 is any amino acid;
X7 is Trp, Bip, Gln, His, Glu (Bzl), 4-Phenylbenzylalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3,4-Cl ₂ ), Phe (4-). OMe), 5-hydroxy -Trp, 6- chloro -Trp, N-MeTrp, α- MeTrp, 1,2,3,4- tetrahydro - _{norharman, Phe (4-CO 2 H} ), Phe (4- CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), Phe (4-tBu), ββ-diPheAla, Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, or above. Is the corresponding α-methylamino acid type of any of the above;
X8 is any amino acid;
X9 is Pen, Cys or hCys;
X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Ph, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, Phe analog or Tyr analog (optionally, Ph (3,4-F ₂ ), Ph (3,4-Cl ₂ ), F (3-Me), Ph [4- (2-aminoethoxy)] , Phe [4- (2- (acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino) ), Ph (4-Me), Ph (4-NH ₂ ), Ph (4-N ₃ ), Ph (4-OMe), or Ph (4-OBzl)), or any of the above. It is an α-methyl amino acid type;
X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), Phe (4-CO ₂ H), βhPhe. (4-F), α-Me-Trp, 4 _{-Phenylcyclohexyl, Phe (4-CF 3} ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5-phenyl), Ph, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7-tri-tert-butyl), Phe (4-Oallyl), Tyr (3-tBu) ), Phe (4-tBu), Phe (4-guanidino, Phe (4-OBzl), Octgly, Glu (Bzl), 4-phenylbenzylalanine, Phe [4- (2-aminoethoxy)], 5-hydroxy -Trp, 6-Chloro-Trp, N-MeTrp, 1,2,3,4-tetrahydro-norhalman, Ph (4-CONH ₂ ), Phe (3,4-OMe ₂ ) Phe (2,3-Cl ₂₎ ), Ph (2,3-F ₂ ), Ph (4-F), 4-Phenylalanine or Bip, or the corresponding α-methyl amino acid type of any of those described above;
X12 is α-MeLys, α-MeOrn, α-MeLeu, α-MeVal, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, MeLeu, Aib, (D) Ala, (D). Asn, (D) Leu, (D) Asp, (D) Ph, (D) Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr Alternatively, it is the corresponding α-methylamino acid type of True, or any of those mentioned above;
X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β- Spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, Spiro -Pip, Thr, Tba, Tlc, Val or Tyr, or the corresponding α-methyl amino acid type of any of those described above;
X14 corresponds to Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, Lys (Ac), Orn, or any of the above. Is an α-methyl amino acid type;
X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys. , Leu, Pro, Gln, Arg or Ser, β-Ala, Arg, or the corresponding α-methylamino acid type of any of those described above;
X16 is absent or the corresponding α-methyl amino acid type of either Gly, Ala, Asp, Ser, Pro, Asn or Thr, or any of those mentioned above;
X17 is absent or is the corresponding α-methyl amino acid type of Glu, Ser, Gly or Gln, or any of those mentioned above;
X18 is absent or any amino acid;
X19 is absent or any amino acid;
X20 is absent or any amino acid)
Contains or consists of an array of.

In certain embodiments of IIa, X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Ph, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, Phe analog or Tyr analog, or the corresponding α-methyl amino acid type of any of those described above; X11 is 2-Nal, 1-Nal, 2,4-dimethyl. Ph, Bip, Phe (3,4-Cl ₂ ), Phe (3,4-F ₂ ), Phe (4-CO ₂ H), βhPhe (4-F), α-Me-Trp, 4-Phenylcyclohexyl , Ph (4-CF ₃ ), α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Nva (5-phenyl), Ph, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7-tri-tert-butyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino, Phe) (4-OBzl), Octgly, Glu (Bzl), 4-Phenylalanine, Phe [4- (2-aminoethoxy)], 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, 1, 2 , 3,4-Tetrahydro-norhalman, Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (2,3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4- F), 4-Phenylalaninealanine or Bip, or the corresponding α-methylamino acid type of any of those described above; Ala, (D) Asn, (D) Leu, (D) Asp, (D) Ph, (D) Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip , Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or the corresponding α-methyl amino acid type of any of those described above; X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Th. r, (D) Ph, Ala, Aib, α-MeLeu, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α -Correspondence to diethyl Gly, Glu, Ph, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, Spiro-pip, Thr, Tba, Tlc, Val or Tyr, or any of the above. X14 is an α-methyl amino acid type; X14 is Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or any of those mentioned above. Is the corresponding α-methylamino acid type of; X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or the corresponding α-methylamino acid type of any of those described above.

In certain embodiments, X3 is present. In certain embodiments, X3 is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln. In certain embodiments, X3 is (D) Arg or (D) Ph. In certain embodiments, X1 and X2 are absent and X3 is present.

In certain embodiments, the X5 is Gln, Ala, Cit, Asp, Dab, Dap, Cit Glu, Ph, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-Me. -Asn, N-Me-Lys, α-Me-Lys, α-Me-Orn, N-Me-Gln, N-Me-Arg, α-MeSer, Orn, Pro, Arg, Ser, Thr, or Val is there. In certain embodiments, the X5 is Gln, Ala, Cit, Asp, Dab, Dap, Glu, Ph, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-Me-. Asn, N-Me-Lys, αMe-Lys, αMe-Orn, N-Me-Gln, N-Me-Arg, Orn, Pro, Arg, Ser, Thr, or Val. In certain embodiments, X5 is Gln or Asn.

In certain embodiments, the X6 is Thr, Asp, Glu, The, Asn, Pro, Arg, or Ser.

In certain embodiments, X7 is Trp.

In certain embodiments, the X8 is Gln, Glu, Ph, Lys, Asn, Pro, Arg, Val, Thr, or Trp.

In certain embodiments, X10 is a Tyr analog or a Ph analog. In certain embodiments, X10 is a Ph analog.

In certain embodiments where X10 is a Phe analog, X10 is hPhe, Phe (4-OMe), α-Me-Phe, hPhe (3,4-dimethoxy), Phe (4-CONH ₂ ), Phe (4-phenoxy), Phe (4-guanadino), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-OBzl), Phe (4-NH ₂ ), Phe (4-F), Phe (3,5 DiF), Phe (CH ₂ CO ₂ H), Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), ββ -DiPheAla, Phe (4-N ₃ ) and Phe [4- (2-aminoethoxy)] are selected. In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In certain embodiments, X10 is Phe (4-OMe), Phe (4-CONH ₂ ) or Phe [4- (2-aminoethoxy)]. In certain embodiments where X10 is a Phe analog, X10 is hPhe, Phe (4-OMe), α-Me-Phe, hPhe (3,4-dimethoxy), Phe (4-CONH ₂ ), Phe (4-phenoxy), Phe (4-guanadino), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-OBzl), Phe (4-NH ₂ ), Phe (4-F), Phe (3,5 DiF), Phe (CH ₂ CO ₂ H), Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), ββ -DiPheAla, Phe (4-N ₃ ) and Phe [4- (2-aminoethoxy)] are selected. In certain embodiments, X10 is Ph (4-OMe).

In certain embodiments where X10 is a Tyr analog, X10 is hTyr, α-MeTyr, N-Me-Tyr, Tyr (3-tBu), Phe (4-CONH ₂ ), Phe [4- ( 2-Aminoethoxy)], and bhTyr. In certain embodiments where X10 is a Tyr analog, X10 is selected from hTyr, α-MeTyr, N-Me-Tyr, Tyr (3-tBu), and bhTyr.

In certain embodiments, X10 is Tyr, Phe (4-OMe), Phe [4- (2-aminoethoxy)], Phe (4-CONH ₂ ), or 2-Nal. In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In certain embodiments, X10 is not Tyr.
In certain embodiments, X11 is a Trp analog. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X11 is 2-Nal.

In certain embodiments, the X12 is Aib, α-MeLys or α-MeLeu.

In certain embodiments of peptide inhibitors of formula II, one or both of X4 and X9 are Pens. In certain embodiments, both X4 and X9 are Pens.

In certain embodiments, the peptide inhibitor of formula II is cyclized. In certain embodiments, the peptide inhibitor of formula II is cyclized by an intramolecular bond between X4 and X9. In certain embodiments, the intramolecular bond is a disulfide bond. In certain embodiments, both X4 and X9 are Pens.

In certain embodiments, the peptide inhibitor of formula II is linear or non-cyclized. In certain embodiments of the linear peptide inhibitor of formula I, X4 and / or X9 are any amino acids.

In certain embodiments of peptide inhibitors of formula II, one or more, two or more, or all three of X1, X2, and X3 are absent. In certain embodiments, X1 is absent. In certain embodiments, X1 and X2 are absent. In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments of peptide inhibitors of formula II, one or more of X16, X17, X18, X19 and X20, two or more, three or more, four or more, or all of them are absent. In certain embodiments of peptide inhibitors of formula I, one or more of X17, X18, X19 and X20, two or more, three or more, or all of them are absent. In certain embodiments, one or more, two or more, or all three of X17, X19 and X20 are absent. In certain embodiments, one or more of X1, X2 and X3 are absent; one or more of X17, X18, X19 and X20, two or more, three or more, or four. not exist.

In certain embodiments of the peptide inhibitor of formula II, X18 is (D) -Lys. In certain embodiments, X18 is (D) -Lys and X17 is absent.

In certain embodiments of the peptide inhibitor of formula II, the peptide inhibitor has the following characteristics: X5 is Asn, Arg or Gln; X6 is Thr; X7 is Trp; And X8 include one or more of being Grn, two or more, three or more, or four. In certain embodiments of the peptide inhibitor of formula I, X4 is Pen; X5 is Gln, Asn or Arg; X6 is Thr; X7 is Trp, 5-hydroxy-Trp, 6 -Chloro-Trp, N-MeTrp, Alpha-Me-Trp, or 1,2,3,4-tetrahydro-norhalman; X8 is Gln; X9 is Pen. In certain embodiments, X5 is Gln. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, both X4 and X9 are Pens.

In certain embodiments of the peptide inhibitor of formula II, the peptide inhibitor has the following characteristics: X10 is Tyr, Phe analog, Tyr analog or 2-Nal; X11 is Trp, 5-hydroxy. -Trp, 6-chloro-Trp, N-MeTrp, alpha-Me-Trp, 1,2,3,4-tetrahydro-norhalman, 2-Nal or 1-Nal; X12 is Aib, α-MeLys , Α-MeOrn and α-MeLeu; X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn; X15 is Gly, Ser or Ala; and X16 comprises one or more of non-existent or AEA, two or more, three or more, four or more, five or more, six or more, or seven. In certain embodiments, X10 is Tyr, Phe (4-OMe), Phe [4- (2-aminoethoxy)], Phe (CONH ₂ ), or 2-Nal. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X10 is not Tyr. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, both X4 and X9 are Pens.

In certain embodiments of the peptide inhibitor of formula II, the peptide inhibitor has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 is , Gln; X10 is a Phe analog; X11 is Trp, 2-Nal or 1-Nal; X12 is Aib, α-MeLys or α-MeOrn; X13 is , Lys, Glu or Lys (Ac); X14 is Asn; X15 is Gly, Ser or Ala; and X16 is one of the absence or AEA. Alternatively, it includes a plurality, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 pieces. In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, both X4 and X9 are Pens.

In certain embodiments of the peptide inhibitor of formula II, the peptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Tyr, Phe analog or 2-Nal; X11 is Trp, 2-Nal or 1-Nal; X12 is Arg, α -MeLys, α-MeOrn, or α-MeLeu; X13 is Lys, Glu or Lys (Ac); X14 is Phe or Asn; X15 is Gly, Ser or Ala; X16 is ,not exist. In certain embodiments, X10 is Tyr, Phe (4-OMe), Phe [4- (2-aminoethoxy)], Phe (4-OMe) or 2-Nal. In certain embodiments, X10 is Ph (4-OMe). In certain embodiments, X10 is not Tyr. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments of the peptide inhibitor of formula II, the peptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Tyr, Phe (4-OMe) or 2-Nal; X11 is Trp, 2-Nal or 1-Nal; X12 is Arg, α-MeLys or α-MeOrn; X13 is Lys, Glu or Lys (Ac); X14 is Phe or Asn; X15 is Gly; X16 is absent. In certain embodiments, X10 is Ph (4-OMe). In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments of the peptide inhibitor of formula II, the peptide is cyclized via X4 and X9; X4 and X9 are Pen; X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln; X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]; X11 is Trp, 2-Nal or 1-Nal. X12 is α-MeLys, α-MeOrn, or α-MeLeu; X13 is Lys, Glu or Lys (Ac); X14 is Asn; X15 is Gly, Ser or Ala. X16 does not exist. In certain embodiments, X10 is Ph (4-OMe). In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments of peptide inhibitors of formula II, X10 is not Tyr.

In certain embodiments, the present invention is optionally 8 to 35 amino acids, 8 to 20 amino acids, 8 to 16 amino acids or 8 to 12 amino acids in length and is optionally cyclized to formula IIb:
Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)] (IIb) (SEQ ID NO: 1403)

(In the formula, Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues; Xaa10 is a Phe analog).
A peptide comprising or consisting of the core sequence of, which inhibits the binding of IL-23 to IL-23R. In certain embodiments, the X10 is α-Me-Phe, Phe (4-OMe), Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-). Cl ₂ ), Phe (4-tBu), Phe (4-NH ₂ ), Phe (4-Br), Phe (4-CN), Phe (4-CO ₂ H), Phe [4- (2-Amino) Ethoxy)] or Phe analog selected from Phe (4-guanadino). In certain embodiments, Xaa10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In one embodiment, Xaa10 is Ph (4-OMe). In certain embodiments, the peptide is cyclized by an intramolecular bond between Pen in Xaa4 and Pen in Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula II, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptide of formula IIb further comprises an amino acid attached to the N-terminal Pen residue. In certain embodiments, the bound amino acid is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Phe, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, the bound amino acid is (D) Arg or (D) Ph.

In certain embodiments, the present invention is optionally 8 to 35 amino acids, 8 to 20 amino acids, 8 to 16 amino acids, or 8 to 12 amino acids in length and is optionally cyclized and of formula IIc. :
Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)] (IIc) (SEQ ID NO: 1404)

(In the formula, Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues; Xaa10 is Tyr, Phe analog, α-Me-Tyr, α-Me-Trp or 2-Nal).
A peptide comprising or consisting of the core sequence of, which inhibits the binding of IL-23 to IL-23R. In certain embodiments, the X10 is Tyr, Phe (4-OMe), Phe [4- (2-aminoethoxy)], α-Me-Tyr, α-Me-Phe, α-Me-Trp or 2 -Nal. In certain embodiments, Xaa10 is Tyr, Phe (4-OMe), Phe (CONH ₂ ), Phe [4- (2-aminoethoxy)] or 2-Nal. In certain embodiments, Xaa10 is Tyr, Phe (4-OMe), Phe [4- (2-aminoethoxy)] or 2-Nal. In certain embodiments, Xaa10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In one embodiment, Xaa10 is Ph [4- (2-aminoethoxy)] or Phe (CONH ₂ ). In certain embodiments, Xaa10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)]. In one embodiment, Xaa10 is Ph [4- (2-aminoethoxy)]. In certain embodiments, Xaa10 is not Tyr. In certain embodiments, the peptide is cyclized by an intramolecular bond between Pen in Xaa4 and Pen in Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula II, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptide of formula IIc further comprises an amino acid attached to the N-terminal Pen residue. In certain embodiments, the bound amino acid is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Phe, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, the bound amino acid is (D) Arg or (D) Ph.

In certain embodiments, the present invention is optionally 8 to 35 amino acids, 8 to 20 amino acids, 8 to 16 amino acids or 8 to 12 amino acids in length and is optionally cyclized to formula IId:
Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Phe [4- (2-aminoethoxy)]-[2-Nal] (IId) (SEQ ID NO: 1405)

(In the formula, Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues)
Contains or comprises peptides consisting of the core sequence of. In certain embodiments, the peptide comprises a disulfide bond between Xaa4 and Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula I, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptide of formula IId further comprises an amino acid attached to the N-terminal Pen residue. In certain embodiments, the bound amino acid is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Phe, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, the bound amino acid is (D) Arg or (D) Ph.

In certain embodiments of the peptide inhibitor of formula II, the peptide inhibitor has the structure shown in any of Tables 2, 3, 4A, 4B, 8, 11 or 15, or Tables 2, 3, ,. Contains the amino acid sequences set forth in 4A, 4B, 8, 11 or 15.

Exemplary Peptide Inhibitors Containing Thioether Bonds In certain embodiments, the present invention comprises a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof, the peptide inhibitor. Is Equation III:

R ^1- X-R ² (III)

(In the formula, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alkyl sulfonate, acid, γ added to the N-terminus. -Glu or pGlu, including a pegged version (eg, 200 Da-60,000 Da) as a spacer, either alone or as described above;

R ² is bound, OH or NH ₂ ;

X is an amino acid sequence of 8 to 20 amino acids or 8 to 35 amino acids)
Has the structure of.

In certain embodiments of the peptide inhibitor of formula III, X is of formula IIIa:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (IIIa)
(SEQ ID NO: 1407)
(During the ceremony,
X1 is absent or any amino acid;
X2 is absent or any amino acid;
X3 is absent or any amino acid;
X4 is Abu, Pen, or Cys;
X5 is any amino acid;
X6 is any amino acid;
X7 is Trp, Bip, Gln, His, Glu (Bzl), 4-Phenylbenzylalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3,4-Cl ₂ ), Phe (4-). OME), 5-hydroxy-Trp, 6-chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norhalman, Phe (4-CO ₂ H), Phe (4-CONH ₂₎ ), Ph (3,4- (OCH ₃ ) ₂ ), Ph (4-CF ₃ ), ββ-diPheAla, Ph (4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly, Or the corresponding α-methylamino acid type of any of the above;
X8 is any amino acid;
X9 is Abu, Pen, or Cys;
X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Ph, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, Phe analog or Tyr analog (optionally, Ph (3,4-F ₂ ), Ph (3,4-Cl ₂ ), F (3-Me), Ph [4- (2-aminoethoxy)] , Phe [4- (2- (acetyl-aminoethoxy)], Phe (4-Br), Phe (4-CONH ₂ ), Phe (4-Cl), Phe (4-CN), Phe (4-guanidino) ), Phe (4-Me), Phe (4-NH ₂ ), Phe (4-N ₃ ), Phe (4-OMe), Phe (4-OBzl)), or the corresponding α of any of the above. -Methyl amino acid type;
X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu (Bzl), 4-phenylbenzylalanine, Tic, Phe [4- (2-aminoethoxy)], Ph (3,4-Cl ₂ ), Phe (3,4-F ₂ ), βhPhe (4-F), Phe (4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-tetrahydro-norhalman, Phe (4-CO ₂ H), Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), Phe (2,3-Cl ₂ ), Phe (3,4-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalanine, α-MePhe, βhNal, βhPhe , ΒhTyr, βhTrp, Bip, Nva (5-phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe (4-Me), Trp (2,5,7-tri-tertbutyl), Phe (4) -O allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl), or Octgly, or the corresponding α-methyl amino acid type of any of those described above. Is;
X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3 -Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, Amino-4-carboxy-tetrahydropyran (THP), Achc, Accc, Acbc, Acvc, Aib, or the corresponding α-methylamino acid type of either of those mentioned above;
X13 is Lys Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Ph, Ala, Aib, α-MeLeu, βAla, βhGlu, βhAla, βhLeu, βhVal, β-spiro. -Pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, Spiro-pip, Thr, Tba, Tlc, Val or Tyr, or the corresponding α-methylamino acid type of any of those described above;
X14 corresponds to Asn, Glu, Ph, Gly, His, Lys, Lys (Ac), Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic, Asp or Tyr, or any of the above. Is an α-methyl amino acid type;
X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys. , Leu, Pro, Gln, Arg, β-Ala, or Ser, or the corresponding α-methylamino acid type of any of those described above;
X16 is absent or the corresponding α-methyl amino acid type of either Gly, Ala, Asp, Ser, Pro, Asn or Thr, or any of those mentioned above;
X17 is absent or is the corresponding α-methyl amino acid type of Glu, Ser, Gly or Gln, or any of those mentioned above;
X18 is absent or any amino acid;
X19 is absent or any amino acid;
X20 is absent or any amino acid)
Contains or consists of an array of.

In certain embodiments, the X14 is Asn, Glu, Ph, Gly, His, Lys, Lys (Ac), Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic, or Tyr, or the aforementioned. Is the corresponding α-methylamino acid type of any of the above.

In certain embodiments of IIIa, X7 is Trp, Bip, Gln, His, Glu (Bzl), 4-Phenylbenzylalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3,4). -Cl ₂ ), Phe (4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp, 1,2,3,4-Tetrahydro-Norhalman, Phe (4-CO ₂₎ H), Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), ββ-diPheAla, Phe (4-tBu), Glu, Gly, Ile, Asn, Pro, Arg , Thr or Octgly, or the corresponding α-methyl amino acid type of any of those described above; X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr. , Glu, Ph, His, Trp, Thr, Tic, Tyr, 4-pyridyl Ala, Octgly, Phe analog or Tyr analog, or the corresponding α-methyl amino acid type of any of those described above; 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, 4-phenylcyclohexyl, Glu (Bzl), 4-phenylbenzylalanine, Tic, Phe [4- (2-aminoethoxy)], Phe (3) , 4-Cl ₂ ), Phe (3,4-F ₂ ), βhPhe (4-F), Phe (4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, α-MeTrp , 1,2,3,4-tetrahydro-norhalman, Ph (4-CO ₂ H), Phe (4-CONH ₂ ), Phe (3,4-dimethoxy), Phe (4-CF ₃ ), Phe (2) , 3-Cl ₂ ), Phe (2,3-F ₂ ), Phe (4-F), 4-Phenylalanine, α-MePhe, βhNal, βhPhe, βhTyr, βhTrp, Bip, Nva (5-phenyl) , Ph, His, hPhe, Tqa, Trp, Tyr, Phe (4-Me), Trp (2,5,7-tri-tertbutyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu), Ph (4-guanidino), Ph (4-OBzl), or Octgly, or the corresponding α-methylamino acid type of any of those described above; X12 is α-MeLy. s, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Ph, (D) Thr, 3-Pal, Aib, β-Ala, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethylGly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn , N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, or the corresponding α-methylamino acid type of any of those described above; X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Ph, Ala, Aib, α-MeLeu, βAla, βhGlu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, Spiro-pip, Thr, Tba, Tlc, Val or Tyr , Or the corresponding α-methylamino acid type of any of those described above; X14 is Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic. Alternatively, it is Tyr, or the corresponding α-methylamino acid type of any of those described above; X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D). Ph, (D) Thr, Ala, AEA, Asp, Glu, Ph, Gly, Lys, Leu, Pro, Gln, Arg or Ser, or the corresponding α-methylamino acid type of any of those described above.

In certain embodiments, X3 is present. In certain embodiments, X3 is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, X3 is (D) Arg or (D) Ph.

In certain embodiments, the X5 is Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu, Ph, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-M. -Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Arg, Ser, Thr, or Val.

In certain embodiments, X6 is Thr, Asp, Glu, Ph, Asn, Pro, Arg, Ser, or Thr.

In certain embodiments, X8 is Gln, Glu, Ph, Lys, Asn, Pro, Arg, Val, Thr, or Trp.

In certain embodiments, X10 is a Tyr analog or a Ph analog. In certain embodiments, X10 is Phe (4-OMe), Phe (CONH ₂ ) or Phe [4- (2-aminoethoxy)]. In certain embodiments, X10 is a Tyr analog or a Ph analog. In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2-aminoethoxy)].

In certain embodiments where X10 is a Phe analog, X10 is hPhe, Phe (4-OMe), α-MePhe, hPhe (3,4-dimethoxy), Phe (4-CONH ₂ ), Phe ( 4-O-Bzl)), Phe (4-guanadino), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-NH ₂ ), Phe (4-F) , Phe (3,5 DiF), Phe (CH ₂ CO ₂ H), Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF3), ββ-diPheAla, Phe (4- It is selected from N ₃ ) and Ph [4- (2-aminoethoxy)]. In certain embodiments, X10 is Ph [4- (2-aminoethoxy)] or Ph (CONH ₂ ). In certain embodiments, X10 is Ph [4- (2-aminoethoxy)].

In certain embodiments where X10 is a Tyr analog, X10 is selected from hTyr, N-Me-Tyr, Tyr (3-tBu), Phe (4-OMe) and bhTyr. In certain embodiments, X10 is Ph (4-OMe).

In certain embodiments, the X10 is Tyr, Phe (4-OMe), Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl ₂ ), Phe (4-tBu), Phe (4-NH2), Phe (4-Br), Phe (4-CN), Phe (4-carboxy), Phe [4- (2 aminoethoxy)] or Phe (4-) Guanazino). In certain embodiments, X10 is not Tyr.

In certain embodiments, X11 is a Trp or Trp analog. In certain embodiments, X11 is 2-Nal or 1-Nal.

In certain embodiments, the peptide inhibitor of formula III is cyclized. In certain embodiments, the peptide inhibitor is cyclized by an intramolecular bond between X4 and X9. In certain embodiments, the intramolecular bond is a thioether bond.

In certain embodiments, the peptide inhibitor of formula III is linear or non-cyclized. In certain embodiments of the linear peptide inhibitor of formula III, X4 and / or X9 are any amino acids.

In certain embodiments of peptide inhibitors of formula III, one or more, two or more, or all three of X1, X2, and X3 are absent. In certain embodiments, X1 is absent. In certain embodiments, X1 and X2 are absent. In certain embodiments, X1, X2 and X3 are absent.

In certain embodiments of peptide inhibitors of formula III, one or more of X16, X17, X18, X19 and X20, two or more, three or more, four or more, or all of them are absent. In certain embodiments of peptide inhibitors of formula III, one or more of X17, X18, X19 and X20, two or more, three or more, or all of them are absent. In certain embodiments, one or more, two or more, or all three of X17, X19 and X20 are absent. In certain embodiments, one or more of X1, X2 and X3 are absent; one or more of X17, X18, X19 and X20, two or more, three or more, or four. not exist.

In certain embodiments of the peptide inhibitor of formula III, one of X4 or X9 is Abu and the other of X4 or X9 is not Abu. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; and X8 is Gln. Includes one or more, two or more, three or more, or four of the things. In certain embodiments, X5 is Grn, X6 is Thr, X7 is Trp, and X8 is Grn. In certain embodiments, X5 is Gln. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X10 is a Tyr or Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl). ), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl) or Phe (4-Me); X12 is Arg, hLeu, (D). Asn, or any alpha methyl amino acid including Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn Being; X15 is β-Ala, Gln, Gly, Ser, Ala; and X16 is one or more of the absence or AEA, two or more, three or more, 4 Includes 5 or more, 6 or more, or 7 or more. In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X10 is a Tyr or Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl). ), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl) or Phe (4-Me); X12 is Arg, hLeu, (D). Asn, or any alpha methyl amino acid including Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn Being; X15 is Gly, Ser, Ala; and X16 is one or more of non-existent or AEA, 2 or more, 3 or more, 4 or more, 5 or more , 6 or more, or 7 or more. In certain embodiments, the Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl ₂ ), Phe (4-tBu). , Phe (4-NH2), Phe (4-Br), Phe (4-CN), Phe (4-carboxy), Phe [4- (2 aminoethoxy)] or Phe (4-guanadino). In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X10 is a Tyr or Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl). ), Tyr (3-tBu), Phe (4-tBu), Phe (4-guanidino), Phe (4-OBzl) or Phe (4-Me); X12 is Arg, hLeu, (D). Asn, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn , Α-MeSer, α-MeVal; X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn; X15 is Gly; and X16 is present Includes one or more, two or more, three or more, four or more, five or more, six or more, or seven of which are not or are AEA. In certain embodiments, the Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl2), Phe (4-tBu), Phe (4-NH ₂ ), Phe (4-Br), Phe (4-CN), Phe (4-carboxy), Phe (4- (2 aminoethoxy)) or Phe (4-guanadino). In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 is Gln. That; X10 is a Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl), Tyr (3-tBu), Phe (4-tBu), Phe ( 4-guanidino), Phe (Bzl) or Phe (4-Me); X12 is Aib, α-MeLys, α-MeLeu, 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeSer, α-MeVal, α-MeOrn; X13 is Lys, Glu or Being Lys (Ac); X14 is Ph or Asn; X15 is β-ala, Gly, Ser, Ala; and X16 is one of the absence or AEA. Includes one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or eleven. In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 is Gln. That; X10 is a Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl), Tyr (3-tBu), Phe (4-tBu), Phe ( 4-guanidino), Phe (Bzl) or Phe (4-Me); X12 is Aib, α-MeLys, α-MeLeu or α-MeOrn; X13 is Lys, Glu or Lys (Ac) ); X14 is Ph or Asn; X15 is Gly, Ser, Ala; and X16 is one or more of absent or AEA. Includes 3, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 pieces. In certain embodiments, the Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe [4- (2 aminoethoxy)], Phe (4-CONH ₂ ), Phe (3,4). _{-Cl 2), Phe (4-} tBu), Phe (4-NH 2), Phe (4-Br), Phe (4-CN), Phe (4-CO 2 H), or Phe (4-guanadino) Is. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 is Gln. That; X10 is a Tyr or Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl), Tyr (3-tBu), Phe (4-tBu), Being Ph (4-guanidino), Phe (Bzl) or Phe (4-Me); X12 is Arg, hLeu, (D) Asn, 4-amino-4-carboxy-tetrahydropyran, Achc, Accc, Acbc , Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeSer, α-MeVal; X13 is Lys, Glu or Lys (Ac). Being; X14 is Ph or Asn; X15 is β-Ala, Asn or Gly; and X16 is one or more of absent or AEA. Includes 3, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 pieces. In certain embodiments, the peptide inhibitor of formula III has the following characteristics: X5 is Arg or Gln; X6 is Thr; X7 is Trp; X8 is Gln. That; X10 is a Tyr or Phe analog; X11 is Trp, 2-Nal, 1-Nal, Phe (4-O-allyl), Tyr (3-tBu), Phe (4-tBu), Being Ph (4-guanidino), Phe (Bzl) or Phe (4-Me); X12 being Arg, hLeu, (D) Asn, α-MeLys, α-MeLeu or α-MeOrn, Aib X13 is Lys, Glu or Lys (Ac); X14 is Ph or Asn; X15 is Gly; and X16 is one of the absence or AEA. Includes one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or eleven. In certain embodiments, the Phe analogs are Phe (4-OBzl), Phe (4OMe), Phe (4-CONH ₂ ), Phe (3,4-Cl ₂ ), Phe (4-tBu), Phe. (4-NH ₂ ), Phe (4-Br), Phe (4-CN), Phe (4-CO ₂ H), Phe (4- (2-aminoethoxy)) or Phe (4-guanidino). .. In certain embodiments, X11 is 2-Nal or 1-Nal. In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X4 is Abu and X9 is Cys.

In certain embodiments, the present invention is a peptide of 8-20 amino acids, 8-16 amino acids or 8-12 amino acids, optionally cyclized, in formula IIIb:
Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9-Xaa10-Xaa11 (IIIb) (SEQ ID NO: 1408)

(In the formula, Xaa4 and Xaa9 are independently selected from Abu and Cys, respectively, and Xaa4 and Xaa9 are not necessarily the same; Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues; Xaa10 is Tyr, Phe analog or 2-Nal, and Xaa11 is 2-Nal or Trp)
Contains or comprises a peptide comprising the core sequence of IL-23, which inhibits the binding of IL-23 to IL-23R. In certain embodiments, Xaa10 is Phe (4-OMe), 2-Nal, or Phe [4- (2-aminoethoxy)]. In one embodiment, Xaa10 is Ph (4-OMe). In one embodiment, Xaa7 is Ph [4- (2-aminoethoxy)]. In one embodiment, Xaa11 is 2-Nal. In certain embodiments, the peptide is cyclized via Xaa4 and Xaa9. In certain embodiments, the Ph analog is Ph [4- (2 aminoethoxy)] or Ph (4-OMe). In certain embodiments, Xaa4 is Abu, Xaa9 is Cys, and the peptide is cyclized via Xaa4 and Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula III, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptides of formula IIIb are Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, or (D) bound to Xaa4. Includes Gln. In certain embodiments, this is (D) Arg or (D) The.

In certain embodiments, the present invention is a peptide of 8-20 amino acids, 8-16 amino acids or 8-12 amino acids, optionally cyclized, of formula IIIc:
Abu-Xaa5-Xaa6-Trp-Xaa8-Cys- [Phe (4-OMe)]-(2-Nal) (IIIc) (SEQ ID NO: 1409)

(In the formula, Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues)
Contains or comprises a peptide comprising the core sequence of IL-23, which inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptide is cyclized via Abu in Xaa4 and Cys in Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula III, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptides of formula IIIc are Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Ph, 2-Nal, Thr, Leu, or (D) bound to Abu. Includes Gln. In certain embodiments, this is (D) Arg or (D) The.

In certain embodiments, the present invention is a peptide of 8-20 amino acids, 8-16 amino acids or 8-12 amino acids, optionally cyclized, of formula IIId:
Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Xaa10-Trp (IIId) (SEQ ID NO: 1410)

(In the formula, Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues; Xaa10 is a modified Phe) contains or consists of a core sequence that inhibits the binding of IL-23 to IL-23R. Contains peptides. In certain embodiments, the modified Phs are Phe (4-tBu), Phe (4-guanidino), Phe [4- (2-aminoethoxy)], Phe (4-CO ₂ H), Phe (4-CN). ), Phe (4-Br), Phe (4-NH ₂ ), PHe (CONH ₂ ) or Phe (4-Me). In certain embodiments, the modified Phs are Phe (4-tBu), Phe (4-guanidino), Phe [4- (2-aminoethoxy)], Phe (4-CO ₂ H), Phe (4-CN). ), Phe (4-Br), Phe (4-NH ₂ ), or Phe (4-Me). In one embodiment, Xaa10 is Ph [4- (2-aminoethoxy)] or Phe (4-OMe). In one embodiment, Xaa10 is Ph [4- (2-aminoethoxy)]. In certain embodiments, the peptide is cyclized via Abu in Xaa4 and Cys in Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula III, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptides of formula IIId are Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Ph, 2-Nal, Thr, Leu, or (D) bound to Abu. Includes Gln. In certain embodiments, this is (D) Arg or (D) The.

In certain embodiments, the present invention is optionally 8-20 amino acids, 8-16 amino acids or 8-12 amino acids and is optionally cyclized in formula IIIe:
Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Phe [4- (2-aminoethoxy)]-[2-Nal] (IIIe) (SEQ ID NO: 1411)

A peptide comprising or consisting of a core sequence (where Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues in the formula) is included. In certain embodiments, the peptide is cyclized via Abu in Xaa4 and Cys in Xaa9. In certain embodiments, the peptide is a peptide inhibitor of formula III, and in certain embodiments, X1, X2 and X3 are absent. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R. In certain embodiments, the peptides of formula IIIb are Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Ph, 2-Nal, Thr, Leu, or (D) bound to Abu. Includes Gln. In certain embodiments, this is (D) Arg or (D) The.

In one embodiment, Xaa5 and Xaa8 are Gln. In one embodiment, Xaa6 is Thr. In certain embodiments, the peptide is cyclized via Abu in Xaa4 and Cys in Xaa9.

In certain embodiments of the peptide inhibitor of formula III, the peptide inhibitor has the structure shown in any of Tables 5A-5C or comprises an amino acid sequence set forth in Tables 5A-5C.

In certain embodiments, the present invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate thereof, of formula (Vf):
X1-X2-X3-Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Vf) (SEQ ID NO: 1412)
(During the ceremony,
X1 does not exist;
X2 is absent or X2 is D-Asp, E, R, D-Arg, F, D-Phe, 2-Nal, T, L, D-Gln, or D-Asn;
X3 is D-Arg;
X5 is N, Q, Cit, Lys, or Lys conjugate (eg, Lys (IVA), Lys (biotin), Lys (octanyl), Lys (Palm), Lys (PEG), Lys (PEG8), Lys ( PEG11-Palm), Lys (Ac));
X6 is T, S or V;
X7 is W, 1-Nal, or 2-Nal;
X8 is Q, Cit, N, Aib or Lys (Ac);
X10 is Ph [4- (2-aminoethoxy)], Phe [4- (2-acetylaminoethoxy)] or Phe (4-CONH ₂ );
X11 is 2-Nal;
X12 is 4-amino-4-carboxy-tetrahydropyran, Aib, αMeLeu, αMeLys, or αMeLys conjugate (eg, αMeLys (Ac), αMeLys (PEG4-Palm), αMeLys (PEG4-lauryl), αMeLys (PEG4 iso)). GluPalm), αMeLys (PEG4 isoGlulauryl), αMeLys (IVA), αMeLys (biotin), or αMeLys (octanyl));
X13 is a Q, E, Cit or Lys conjugate (eg, Lys (Ac), Lys (PEG4-isoGlu-Palm), Lys (PEG4-octanyl), Lys (PEG4-Palm), Lys (biotin), Lys. (Octanyl), Lys (Palm), Pys (PEG8), or Lys (PEG11-Palm));
X14 is an N, Cit, Q, L, G, S, Aib, F, 2-Nap, N-Me-Ala, R, W, nLeu, Tic or Lys conjugate (eg, Lys (Ac)). ;
X15 is N, Cit, Q, βAla, Lys (Ac) or Aib;
X16, X17, X18, X19 and X20 do not exist)
Provided is a peptide inhibitor containing the amino acid sequence of.
In certain embodiments, X2 is D-Asp, E, R, D-Arg, F, D-Phe, 2-Nal, T, L, D-Gln, or D-Asn.

In certain embodiments, the present invention is a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate thereof, of formula (Vh):
X1-X2-X3-Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Vh) (SEQ ID NO: 1413)
(During the ceremony,
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any D-amino acid or is absent;
X4 is a chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, Ser, hSer or X9;
X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser, Glu or Thr. Yes;
X6 is Thr, Ser, Asp, Ile or any amino acid;
X7 is Trp, 6-chloro-Trp, 1-Nap or 2-Nap;
X8 is Glu, Gln, Asn, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), or Lys (N-ε-palmitoyle). ;
X9 is any amino acid or chemical moiety capable of forming a bond with Cys, hCys, Pen, hPen, Abu, or X4;
X10 is a 2-Nal, Phe analog, Tyr, or Tyr analog;
X11 is 1-Nal, 2-Nal, Phe (3,4-dimethoxy), 5-hydroxyTrp, Phe (3,4-Cl2), Trp or Tyr (3-tBu);
X12 is Aib, 4-amino-4-carboxy-tetrahydropyran, any alpha-methyl amino acid, alpha-ethyl-amino acid, Achc, Acvc, Acbc, Accc, 4-amino-4-carboxy-piperidine, 3-Pal. , Agp, □ -diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cav, Cha, Cit, Cpa, D-Asn, Glu, His , HLeu, hArg, Lys, Leu, Octgly, Orn, Piperidine, Arg, Ser, Thr or THP;
X13 is Lys (Ac), Gln, Cit, Glu, or any amino acid;
X14 can be Asn, Gln, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyle-L-γ-glutamyl)), Lys (N-ε-palmityl), Asp, or any Is an amino acid;
X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib, Asp or Cit;
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or does not exist)
Provided is a peptide inhibitor containing the amino acid sequence of.

In certain embodiments of any of the peptide inhibitors described herein, including but not limited to those of formulas (If) and (Ih), the peptide inhibitors are of X4 and X9. It is cyclized by a bond between them, for example a thioether bond. In certain embodiments, the peptide inhibitor inhibits the binding of interleukin 23 (IL-23) to the IL-23 receptor.

In certain embodiments, X1, X2 and X3 are absent. In certain embodiments, X1 and X2 are absent. In certain embodiments, X1 is a D-amino acid or is absent. In certain embodiments, X2 is a D-amino acid or is absent.

In certain embodiments, the X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg. , Ser, or Thr.

In certain embodiments, X5 is N, X6 is T, X7 is W, or X8 is Q. In certain embodiments, X5 is N, X6 is T, X7 is W, and X8 is Q.

In certain embodiments, X5 is Q, X6 is T, X7 is W, or X8 is Q. In certain embodiments, X5 is Q, X6 is T, X7 is W, and X8 is Q.

In certain embodiments, X5 is N, X6 is T, X7 is W, and X8 is Cit.

In certain embodiments, X10 is Ph [4- (2-aminoethoxy)].

In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran, Aib, αMeLeu, or αMeLys. In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran.

In certain embodiments, X13 is E or Lys (Ac). In certain embodiments, X13 is Lys (Ac).

In certain embodiments, the X14 is Asn, Gln, Lys (Ac), Cit, Cav, Lys (N-ε- (N-α-palmitoyl-L-γ-glutamyl)), Lys (N-ε-). Palmitoyl), or any amino acid.

In certain embodiments, X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib, or Cit.

In certain embodiments, X14 is N.

In certain embodiments, X15 is N.

In certain embodiments, X16 is a D-amino acid or is absent. In certain embodiments, X17 is a D-amino acid or is absent. In certain embodiments, X18 is a D-amino acid or is absent. In certain embodiments, X19 is a D-amino acid or is absent. In certain embodiments, X20 is a D-amino acid or is absent.

In certain embodiments, X2 is absent; X3 is absent; X5 is Q, X6 is T, X7 is W, and X8 is Q; X10 is Ph [4- (2-aminoethoxy)]; X12 is 4-amino-4-carboxy-tetrahydropyran, Aib, αMeLeu, or αMeLys; X13 is E or Lys (Ac). Yes; X14 is N; X15 is N. In certain embodiments, X12 is 4-amino-4-carboxy-tetrahydropyran and X13 is Lys (Ac).

In certain embodiments, any of the amino acids in the peptide inhibitor are linked by a linker moiety, such as PEG.

In certain embodiments, the N-terminus of the peptide inhibitor comprises an Ac group.

In certain embodiments, the C-terminus of the peptide inhibitor _{comprises two} NH groups.

In certain embodiments, the present invention comprises peptides comprising or consisting of the amino acid sequences shown in either Table 4 or Table 5, or structures shown in either Table 4 or Table 5. Includes peptide inhibitors containing or consisting of (or pharmaceutically acceptable salts thereof). In certain embodiments, the peptide does not contain a conjugate moiety, but contains an Abu residue. In certain embodiments, the peptide or inhibitor is between the two Abu and Cys residues, or the two outermost in square brackets after the term "cyclo" indicating the presence of a cyclic structure. Includes a thioether bond between the amino acids. In certain embodiments, the inhibitor is acetate. The peptide sequences of the exemplary inhibitors are shown in Tables 4 and 5 from the N-terminus to the C-terminus, with the conjugate moiety and both the N-terminus Ac group and / or the C-terminus NH ₂ groups. The cyclic structure is indicated by "cyclo" as illustrated in Table 5, indicating the presence of a thioether bond between Abu at X4 and Cys at X9 in square brackets.

Exemplary Peptide Inhibitors Containing Cyclic Amides In certain embodiments, the invention comprises a peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvent compound thereof, which inhibits this peptide. The agent is of formula IV:

R ^1- X-R ² (IV)

(In the formula, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, alone or as a spacer of any of those described above. Includes pegged version;

R ² is bound, OH or NH ₂ ;

X is the formula IVa:
X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (IVa) (SEQ ID NO: 1428)

(During the ceremony,
X1 is absent or any amino acid;
X2 is absent or any amino acid;
X3 is absent or any amino acid;
X4 is Dap, Dab, Glu, Asp, (D) -Asp or (D) -Dab;
X5 is Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu, Ph, Gly, His, hCys, Cys, Leu, Met, Asn, N-Me-Ala, N-M-Asn, N-Me. -Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Arg, Ser, Thr, or Val;
X6 is Thr, Asp, Glu, Ph, Asn, Pro, Arg, Ser, or Thr;
X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly;
X8 is Gln, Glu, Ph, Lys, Asn, Pro, Arg, Thr, or Trp;
X9 is Dap, Dab, Glu, Asp, (D) -Asp or (D) -Dab;
X10 is Tyr (OMe) Phe (4-OMe), 1-Nal, 2-Nal, Aic, a-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr), Glu, Phe, His. , HPhe (3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH ₂ ), Phe (4-phenoxy), Thr, Tic, Tyr, Tyr (3-tBu), Phe ( 4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-NH ₂ ), Phe (4-F), Phe (3,5-F ₂ ), Phe (Penta-F) , Ph (3,4-Cl ₂ ), Ph (4-CF ₃ ), Bip, Cha, 4-pyridylalanine, βhTyr, OctGly, Ph (4-N ₃ ), Ph (4-Br) or Ph [4 -(2-Aminoethoxy)];
X11 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,5-F ₂ ), Phe (4-CONH ₂ ), Phe ( 4-F), 4 _{-Phenylalaninealanine, Phe (4-CF 3} ), α-MePhe, βhPhe, βhTyr, βhTrp, BIP, Nva (5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7-tri-tertbutyl), Phe (4-Oallyl), Tyr (3-tBu), Phe (4-tBu) ), Ph (4-guanidino), Tyr (Bzl), or OctGly;
X12 is α-MeLys, α-MeOrn, α-MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Ph, (D) Thr, 3-Pal. , Aib, β-Ala, β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr Tle, 4-amino-4-carboxy-tetrahydropyran, Achc Acpc, Acbc, Acvc, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeSer, α-MeVal;
X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, Aib, β-Ala, β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Lys (Ac), Leu, Asn, Ogl, Pro, Gln, Arg, Ser, β-spiro-pip, Thr, Tba, Tlc, Val or Tyr;
X14 is Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr;
X15 is β-ala, Asn, Gly, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Thr, Ala, AEA, Asp, Glu, Phe. , Gly, Lys, Leu, Pro, Gln, Arg or Ser;
X16 is absent or is Gly, Ala, Asp, Ser, Pro, Asn or Thr;
X17 is absent or Glu, Ser, Gly or Gln;
X18 is absent or any amino acid;
X19 is absent or any amino acid;
X20 is absent or any amino acid)
An amino acid sequence of 8 to 20 amino acids containing or consisting of the sequence of)
Has the structure of.

In certain embodiments of IVa, X12 comprises α-MeLys, α-MeOrn, α-MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe. , (D) Thr, 3-Pal, Aib, β-Ala, β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe , HLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Grn, Arg, Ser, Thr or Tle; X13 is Lys (Ac), ( D) Asn, (D) Leu, (D) Thr, (D) Ph, Ala, Aib, α-MeLeu, Aib, β-Ala, β-Glu, βhAla, βhLeu, βhVal, β-spiro-pip, Cha , Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Ph, hLeuLys, Leu, Asn, Ogl, Pro, Gln, Arg, Ser, β-spiro-pip, Thr, Tba, Tlc, Val or Tyr. Yes; X14 is Asn, Glu, Ph, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr; X15 is Gly, (D) Ala, ( D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Thr, Ala, AEA, Asp, Glu, Ph, Gly, Lys, Leu, Pro, Grn, Arg or Ser.

In a particular embodiment of the peptide inhibitor of formula (IV), X5 is Cys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-. Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val; X6 is Glu, Arg, Ser; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly; X8 is Ph, Asn, Pro, Arg, Thr, Trp; X10 is Ph (4-OMe), 1-Nal, 2-Nal. , Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4- CONH ₂ ), The- (4-phenoxy), Thr, Tic, Tyr (3-tBu), The (4-tBu), The (4-CN), The (4-Br), The (4-NH ₂₎ ), Phe (4-F), Phe (3,5-F ₂ ), PheCH ₂ CO ₂ H, Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), Bip, Cha, 4-pyridylalanine, βhTyr, OctgGly, Tyr (4-N ₃ ), Phe (4-Br), Phe [4- (2-aminoethoxy)]; X11 is 2-Nal, 1 -Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,5-F ₂ ), Phe (4-CONH ₂ ), Phe (4-F), 4-Phenyl Cyclohexyl, Phe (4-CF ₃ ), α-MePhe, Nal, βhPhe, βhTyr, βhTrp, BIP, Nva (5-phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe (4-OMe), The (4-Me), Tyr (2,5,7-tri-tert-butyl), The (4-Oallyl), The (3-tBu), The (4-tBu), The (4-guanidino) , Tyr (Bzl), OctGly; X12 is α-Me-Lys, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal, β-spi Lo-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tre, 4-amino-4-carboxy-tetrahydropyran, AchcAcpc, Acbc, Acvc, α-diethyl Gly, α-MeLys (Ac), α-MeSer, α-MeVal; X13 is Lys, Lys (Ac), (D) Asn, (D) Leu, (D) Phe, ( D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethylGly, hLeu, Asn, Ogl , Pro, Gln, Ser, Thr, Tba, Tle; X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic; X15 is ( D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Aea, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Asn, Arg or β -Ala; X16 is Gly, Ser, Pro, Asn, Thr; or X17 is Glu, Ser, Gly, Gln.

In a particular embodiment of the peptide inhibitor of formula (IV), X5 is Cys, Cit, Asp, Dab, Dap, Gly, His, hCys, Lys, Met, Asn, N-Me-Ala, N-Me-. Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Val; X6 is Glu, Arg, Ser; X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly; X8 is Ph, Asn, Pro, Arg, Thr, Trp; X10 is Ph (4-OMe), 1-Nal, 2-Nal. , Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4-dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4- CONH ₂ ), The- (4-phenoxy), Thr, Tic, Tyr (3-tBu), The (4-tBu), The (4-CN), The (4-Br), The (4-NH ₂₎ ), Phe (4-F), Phe (3,5-F ₂ ), PheCH ₂ CO ₂ H, Phe (Penta-F), Phe (3,4-Cl ₂ ), Phe (4-CF ₃ ), Bip, Cha, 4-pyridylalanine, βhTyr, OctgGly, Tyr (4-N ₃ ), Phe (4-Br), Phe [4- (2-aminoethoxy)]; X11 is 2-Nal, 1 -Nal, 2,4-dimethylPhe, Bip, Phe (3,4-Cl ₂ ), Phe (3,5-F ₂ ), Phe (4-CONH ₂ ), Phe (4-F), 4-Phenyl Cyclohexyl, Phe (4-CF ₃ ), α-MePhe, Nal, βhPhe, βhTyr, βhTrp, BIP, Nva (5-phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe (4-OMe), The (4-Me), Tyr (2,5,7-tri-tert-butyl), The (4-Oallyl), The (3-tBu), The (4-tBu), The (4-guanidino) , Tyr (Bzl), OctGly; X12 is α-Me-Lys, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Ph, (D) Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala, βhAla, βhArg, βhLeu, βhVal, β-spi Lo-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle; X13 is Lys (Ac), (D) Asn, ( D) Leu, (D) Ph, (D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, βhLeu, βhVal, β-spiro-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, Thr, Tba, Tle; X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic; X15 is (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Aea, Asp, Glu, Phe, Gly, Lys , Leu, Pro, Arg; X16 is Gly, Ser, Pro, Asn, Thr; or X17 is Glu, Ser, Gly, Gln.

In certain embodiments, the peptide inhibitor is cyclized. In certain embodiments, the peptide is cyclized through an intramolecular bond between X4 and X9. In certain embodiments, the intramolecular bond is an amide bond.

In certain embodiments, the peptide inhibitor is linear or non-cyclized.

In certain embodiments of peptide inhibitors of formula IV, one or more, two or more, or all three of X1, X2, and X3 are absent.

In certain embodiments, the X3 is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Phe, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, X3 is (D) Arg or (D) Ph.

In certain embodiments of peptide inhibitors of formula IV, one or more, two or more, or all three of X17, X19 and X20 are absent.

In certain embodiments of the peptide inhibitor of formula IV, X4 is Dap, Dab, or (D) Dab and X9 is Glu, (D) Asp, or Asp. In certain embodiments of peptide inhibitors of formula I, X4 is Glu, (D) Asp or Asp, and X9 is Dab, Dap or (D) Dab.

In certain embodiments of the peptide inhibitor of formula IV, X18 is (D) -Lys. In certain embodiments, X17 is absent and X18 is (D) -Lys.

In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the following characteristics: X5 is Gln; X6 is Thr; X7 is Trp; and X8 is. Includes one or more of Gln, two or more, three or more, or all four.

In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the following characteristics: X10 is Tyr, Phe [4- (2-aminoethoxy)], Phe (4-CONH ₂ ) or Phe (4). -OMe); X11 is 2-Nal or Trp; X12 is 4-amino-4-carboxy-tetrahydropyran, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α- MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, or Arg; X13 is Glu or Lys (Ac); X14 is Asn X15 is Gly, Asn, or β-Ala; and X16 is one or more of being AEA, two or more, three or more, four or more, five or more. , 6 or more, or 7 or more. In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the following characteristics: X10 is Tyr; X11 is Trp; X12 is Arg; X13 is Glu. X14 is Asn; X15 is Gly; and X16 is one or more of being AEA, two or more, three or more, four or more, five. As mentioned above, 6 or more, or 7 are included.

In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the following characteristics: X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln X10 is Tyr; X11 is Trp; X12 is Arg; X13 is Glu or Lys (Ac); X14 is Asn; X15 Is Gly; and X16 is one or more of AEA, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more. , 9 or more, 10 or more, or all of them. In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the following characteristics: X5 is Gln; X6 is Thr; X7 is Trp; X8 is Gln X10 is Tyr; X11 is Trp; X12 is Arg; X13 is Glu; X14 is Asn; X15 is Gly That; and X16 is one or more of AEA, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more 10 Includes more than one or all of them.

In certain embodiments of peptide inhibitors of formula IV, the peptides are cyclized via X4 and X9; X5, X6, X7 and X8 are Gln, Thr, Trp, and Gln, respectively; X10, X11, X12, X13, X14, X15, and X16 are Tyr, Trp, Arg, Glu, Asn, Gly, and AEA, respectively.

In certain embodiments, the present invention is a peptide of 8-20 amino acids, optionally cyclized.
Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9-[Phe (4-OMe)]-[2-Nal] (Formula IVb) (SEQ ID NO: 1429)

(In the formula, Xaa4 and Xaa9 are independently selected from Dap, Dab, Glu, Asp, (D) -Asp and (D) -Dab, respectively, and Xaa4 and Xaa9 form an intramolecular bond, for example, a cyclic amide. It is possible; it comprises or consists of a core sequence comprising (Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residues) and comprises a peptide that inhibits the binding of IL-23 to IL-23R. .. In certain embodiments, the peptide inhibitor is a peptide inhibitor of formula IV. In certain embodiments, the peptide inhibits the binding of IL-23 to IL-23R.

In certain embodiments of the peptide inhibitor of formula IV, the peptide inhibitor has the structures shown in Table 7 or comprises the amino acid sequences listed in Table 7.

Certain exemplary peptide inhibitors of the invention are any of the formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) and (Vh). And also shown in Tables 2-5, where the amino acid sequences of the selected peptide inhibitors are presented. These peptide inhibitors are acetates.

Optional Properties of Peptide Inhibitors Any of the peptide inhibitors of the present invention can be further defined, for example, as follows. It is understood that each of the further defined features described herein can be applied to any peptide inhibitor that allows the presence of further defined features by the amino acids specified at a particular position. Will be done.

In certain embodiments of any of the peptide inhibitors described herein, the peptide inhibitor is cyclized.

In certain embodiments of any of the peptide inhibitors described herein, the peptide inhibitor or monomer subunit thereof is linear or non-cyclized. In certain embodiments where the peptide is linear or non-cyclized, X4 and X9 may be any amino acid.

In certain embodiments, the peptide inhibitor is cyclized through, for example, X4 and X9.

In various embodiments, R ¹ is a bond, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, or C1-C20 alkanoyl, either alone or as described above. Includes a pegged version as a spacer of the, eg, acetyl. It is understood that R ¹ may replace or be present in addition to the typical amine group located at the amino terminus of the peptide. Furthermore, ^{it is understood that R 1} does not have to be present. In certain embodiments, the peptide inhibitor comprises an N-terminus selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, or C1-C20 alkanoyl, alone. Alternatively, a pegged version is included as a spacer of any of those described above, such as acetyl. In any particular embodiment of the peptide inhibitors described herein, R ¹ or N-terminal moiety is hydrogen. In certain embodiments, R ¹ is a bond, eg, a covalent bond.

In certain embodiments of any peptide inhibitor having any of a variety of formulas described herein, R ¹ or N-terminal portion, methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl , Isobutyryl, octanyl, and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanic acid. In one embodiment, ^{R 1} or N-terminal portion is pGlu. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is an acetyl, whereby the peptide inhibitor is capable of capping or protecting, for example, an N-terminal amino acid residue, eg, an N-terminal Pen residue or Abu residue. It is acylated at the terminus.

In certain embodiments of any peptide inhibitors described herein, R ¹ or N-terminal moiety is an acid. In certain embodiment, R ¹ or N-terminal portion, acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, octanoic acid, lauric acid, hexadecanoic acid, 4-biphenyl acetic acid, 4-fluoro Phenylacetic acid, gallic acid, pyroglutamic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartrate acid, citric acid, palmitic acid, benzoic acid , 3- (4-Hydroxybenzoyl) benzoic acid, silicic acid, mandelic acid, 4-methylbicyclo (2.2.2) -oct-2-ene-1-carboxylic acid, glucoheptoic acid, 3-phenylpropionic acid , Trimethylacetic acid, tertiary butylacetic acid, laurylsulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, alkylsulfonic acid and arylsulfonic acid.

In certain embodiments, R ¹ or N-terminal portion, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane - alkyl sulfonic acid selected from disulfonic acid, and 2-hydroxyethane sulfonic acid.

In certain embodiments, R ¹ or N-terminal portion, benzenesulfonic acid, 4-chlorobenzene sulfonic acid, 2-naphthalenesulfonic acid, arylsulfonic acid selected 4-toluenesulfonic acid, and camphorsulfonic acid.

In some embodiments where the peptides of the invention include conjugations with acidic compounds such as isovaleric acid, isobutyric acid, valeric acid, the presence of such conjugations is referred to in the form of acids. .. Thus, but not limited to any form, for example, the conjugation of isovaleric acid with the peptide may be isovaleryl (eg, isovaleryl- [Pen] -QTWQ [Pen]-[Phe (4-OMe)]-[ Instead of indicating by referring to 2-Nal]-[α-MeLys]-[Lys (Ac)]-NG-NH ₂ (SEQ ID NO: 262) , in some embodiments, the present application is such a conjugate. Isovaleryl- [Pen] -QTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NG-NH ₂ (sequence) References to conjugation in the form of an acid, referred to as number 262), are intended to include the forms present in the peptide inhibitor.

In certain embodiments, the peptide inhibitor comprises a C-terminus (eg, R ² or C-terminus portion) _{selected from binding, OH or NH 2.} In certain embodiments, R ² is a bond. In various embodiments of any of the peptide inhibitors having any of the various formulas described herein, the R ² or C-terminal moiety is OH or NH ₂ . It is understood that the R ² or C-terminal moiety may generally be one that replaces or is present in addition to the carboxy group located at the carboxy terminus of the peptide. Furthermore, ^{it is understood that R 2} does not have to be present.

In any particular embodiment of a peptide inhibitor having any of the various formulas described herein, X is 7-35 amino acid residues, 8-35 amino acid residues, 9 ~ 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acids Residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues, 9- Contains or consists of 18 amino acid residues, or 10-18 amino acid residues.

In certain embodiments of any of the formulas described herein, either or both of Xs shall not include or consist of the amino acid sequences described in US Patent Application Publication No. US2013 / 0029907. There is no. In certain embodiments of any of the formulas described herein, either or both of Xs shall not include or consist of the amino acid sequences described in US Patent Application Publication No. US2013 / 0172272. There is no.

In certain embodiments of any of the peptide inhibitors described herein, each of the peptide inhibitor, or monomeric subunit thereof, has at least 3 amino acid residues at the carboxy terminus of the X9 amino acid residue. Contains or consists of at least 4 amino acid residues, at least 5 amino acid residues, at least 6 amino acid residues, or at least 7 amino acid residues. In any particular embodiment of the peptide inhibitors described herein, the peptide inhibitor is a carboxy-terminal 3-11 amino acid residue of the X9 amino acid residue, 3-10 amino acid residues, 3-9. Amino acid residues, 3-8 amino acid residues, 3-7 amino acid residues, 3-6 amino acid residues, 3-5 amino acid residues, 3-4 amino acid residues, 3 amino acid residues, 4 amino acid residues, 5 Includes amino acid residues, 6 amino acid residues, 7 amino acid residues, 8 amino acid residues, 9 amino acid residues, 10 amino acid residues, or 11 amino acid residues.

In certain embodiments of any of the peptide inhibitors described herein, does the peptide inhibitor, or each of its monomer subunits, contain 4 amino acid residues between X4 and X9? , Or consists of it. In one embodiment, both X4 and X9 are cysteines.

In certain embodiments, any peptide inhibitor of the formula described herein comprises an amino acid residue or moiety represented by X4 to X15. In certain embodiments, the peptide inhibitor does not include X1-X3 or X16-X20. In certain embodiments, the peptide inhibitor comprises an N-terminal extension of 1-3 amino acid residues corresponding to any of X1 to X3. In certain embodiments, any one or more of X1, X2 and X3, if present, is a D-amino acid. In certain embodiments, the peptide inhibitor comprises a C-terminal extension of 1-5 amino acid residues corresponding to any of X16-X20. In certain embodiments, any one or more of X16, X17, X18, X19 and X20, if present, is a D-amino acid. Illustrative amino acid residues that may be present at the N-terminal and / or C-terminal extension are shown in Tables 3 and 5. Each of these tables shows the first peptide inhibitor, along with its derivatives, including N-terminal extension, C-terminal extension, and / or conjugate moieties. The present invention includes derivatives of any of the peptide inhibitors described herein, including one or more such N-terminal extensions, C-terminal extensions, and / or conjugate moieties. In certain embodiments, any of the amino acid residues shown at the extended positions in Tables 3 and 5 may be present in any combination within the peptide inhibitors of the invention. In certain embodiments, N-terminal and / or C-terminal elongation is associated with, for example, an increase in half-life when administered to a subject.

In certain embodiments of any of the peptide inhibitors described herein, each of the peptide inhibitor, or monomer subunit thereof, has, for example, an amino acid sequence motif, W-, at positions X7 to X11. Includes XXYW (SEQ ID NO: 1430). In certain embodiments, the peptide inhibitor, or each of its monomer subunits, is located, for example, at positions X4 to X11 with an amino acid sequence motif, C-X-X-W-X-C-Y-W. (SEQ ID NO: 1431) is included. In certain embodiments, the peptide inhibitor, or each of its monomer subunits, is located, for example, at positions X4 to X11 with an amino acid sequence motif, Pen-X-X-W-X-Pen-Y-W. (SEQ ID NO: 1432) is included. In certain embodiments of any of the peptide inhibitors described herein, the peptide inhibitor, or both of its monomer subunits, is located, for example, at positions X7 to X11 with an amino acid sequence motif, W. -X-X-Y-W (SEQ ID NO: 1430) is not included, and in the formula, X is an arbitrary amino acid.

In certain embodiments of any of the formulas or peptide inhibitors described herein, the peptide inhibitor comprises one or more amino acid residues on the N-terminal side of X4. In certain embodiments, X3 is present. In certain embodiments, the X3 is Glu, (D) Glu, Arg, (D) Arg, Ph, (D) Phe, 2-Nal, Thr, Leu, or (D) Gln. In certain embodiments, X3 is (D) Arg or (D) Ph.

In certain embodiments of any of the formulas or peptide inhibitors described herein, the peptide inhibitor comprises an amino acid at position X2. In certain embodiments, X2 is Glu, (D) Asp, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln, or (D) Asn. .. In certain embodiments, X2 and X3 are present. In certain embodiments, X2 is Glu, (D) Asp, Arg, (D) Arg, Ph, (D) Ph, 2-Nal, Thr, Leu, (D) Gln, or (D) As. , X3 is (D) Arg.

In certain embodiments, the peptide inhibitor of the invention, or one or both of its monomeric subunits, optionally at its C-terminus, has the following amino acid sequence:
ENG;
ENN;
[4-Amino-4-carboxy-tetrahydropyran] -ENN (SEQ ID NO: 1433) ;
[Lys (Ac)]-NN;
[Α-MeLys] -ENG (SEQ ID NO: 1434) ;
[Α-MeLys]-[Lys (Ac)]-NN (SEQ ID NO: 1435) ;
[Α-MeLeu]-[Lys (Ac)]-NN (SEQ ID NO: 1436)
[Α-MeLeu] -ENG (SEQ ID NO: 1437) ;
[Α-MeOrn]-[Lys (Ac)]-NG (SEQ ID NO: 1438) ;
[Α-MeLeu] -ENG (SEQ ID NO: 1439) ;
Aib- [Lys (Ac)]-NG (SEQ ID NO: 1440) ;
Aib- [Lys (Ac)]-NN (SEQ ID NO: 1441) ;
NG- [AEA]-[(D) -Lys] (SEQ ID NO: 1442) ;
[Dapa] -NG- [AEA]-[(D) -Lys] (SEQ ID NO: 1443) ;
[Orn] -NG- [AEA]-[(D) -Lys] (SEQ ID NO: 1444) ;
[Α-MeLys] -ENN (SEQ ID NO: 1445) ;
[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN (SEQ ID NO: 1446) ;
[Achc]-[Lys (Ac)]-NN (SEQ ID NO: 1447) ; or [Acpc]-[Lys (Ac)]-NN (SEQ ID NO: 1448)
Including one of them.

In certain embodiments, one of these amino acid sequences constitutes the terminal C-terminal amino acid of the peptide. In certain embodiments, these amino acid sequences correspond to X13-X15 or X12-X15 or X14-X16 or X13-X17.

In certain embodiments, the peptide inhibitor of the invention, or one or both of its monomeric subunits, optionally at its C-terminus, has the following amino acid sequence:
WQCY- [2-Nal]-[α-MeLys] (SEQ ID NO: 1449) ;
WQC- [Phe (4-OMe)]-[2-Nal]-[α-MeLys] (SEQ ID NO: 1450) ;
WQC- [Phe (4-OMe)]-[2-Nal]-[Aib] (SEQ ID NO: 1451) ;
WQ- [Pen]-[Phe (4-OMe)]-[2-Nal]-[α-MeLys] (SEQ ID NO: 1452) ;
W-Xaa8-C-Phe [4- (2-aminoethoxy)]-[2-Nal] (SEQ ID NO: 1453) ;
W-Xaa8-C-Phe [4- (2-aminoethoxy)]-[1-Nal] (SEQ ID NO: 1454) ;
W-Xaa8-C-Phe [4- (2-aminoethoxy)] (SEQ ID NO: 1455) ; or

W-Xaa8-C- [Phe (4-OCH ₃ )] (SEQ ID NO: 1456)
Including one of them. In certain embodiments, one of these amino acid sequences constitutes the terminal C-terminal amino acid of the peptide. In certain embodiments, these amino acid sequences correspond to X7-X12 or X7-X11 or X7-X10.

In certain embodiments of any of the peptide inhibitors described herein, including both the peptide monomer inhibitor and the monomeric subunit of the peptide dimer inhibitor, the peptide monomer. The inhibitor or monomeric subunit is cyclized via a peptide bond between its N-terminal amino acid residue and its C-terminal amino acid residue. In certain embodiments, the peptide inhibitor (or monomeric subunit thereof) has an intramolecular bond between X4 and X9 and a peptide bond between its N-terminal amino acid residue and its C-terminal amino acid residue. Including both. In certain embodiments, the intramolecular bond is any of those described herein, such as a disulfide bond or a thioether bond.

In certain embodiments, the present invention describes the following (shown in the direction from N-terminus to C-terminus):
X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 1457) ;
Pen-X5-X6-W-Q-Pen (SEQ ID NO: 1458) ;
Pen-X5-X6-W-X8-Pen (SEQ ID NO: 1459) ;
Pen-X5-X6-W-X8-Pen- [Phe (4-CONH2)] (SEQ ID NO: 1460) ; and Pen-X5-X6-W-X8-Pen- [Phe [4- (2-aminoethoxy)] ]] (SEQ ID NO: 1461) ,
It comprises a peptide inhibitor comprising a core consensus sequence selected from one of the following, where the Pen residues are bound by an intramolecular bond, eg, a disulfide bond. X1, X2, X3, X5, X6, X8, X10, X11, X12, X13, X14, and X15 may be any amino acid. In some embodiments, X5 is Arg, Asn, Gln, Dap, Orn; X6 is Thr or Ser; X8 is Gln, Val, Ph, Glu, Lys. In certain embodiments, X1, X2, X3, X5, X6, X8, X10, X11, X12, X13, X14, and X15 are any of the various formulas and peptide inhibitors described herein. Defined as described.

In certain embodiments, the present invention describes the following (shown in the direction from N-terminus to C-terminus):
X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 1462) ;
Abu-X5-X6-WQC (SEQ ID NO: 1463) ;
Abu-X5-X6-W-X8-C (SEQ ID NO: 1464) ;
Abu-X5-X6-W-X8-C- [Phe (4-CONH2)] (SEQ ID NO: 1465) ; and Abu-X5-X6-W-X8-C- [Phe [4- (2-aminoethoxy)] ]] (SEQ ID NO: 1466) ,
It comprises a peptide inhibitor comprising a core consensus sequence selected from one of, where Abu and C are linked by an intramolecular thioether bond. X1, X2, X3, X5, X6, X8, X10, X11, X12, X13, X14, and X15 may be any amino acid. In some embodiments, X5 is Arg, Asn, Gln, Dap, Orn; X6 is Thr or Ser; X8 is Gln, Val, Ph, Glu, Lys. In certain embodiments, X1, X2, X3, X5, X6, X8, X10, X11, X12, X13, X14, and X15 are any of the various formulas and peptide inhibitors described herein. Defined as described.

In certain embodiments, any of the peptide inhibitors described herein may be further cyclized by a peptide bond between its N-terminal amino acid residue and its C-terminal amino acid residue. In certain embodiments, the peptide inhibitor has a peptide bond between X3 or X4 and any one of X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19 or X20. Including. In certain embodiments, the peptide inhibitors of the invention comprise a peptide bond between their N-terminal amino acid and C-terminal amino acid residues, as well as an intramolecular bond between X4 and X9. In certain embodiments, the intramolecular bond is either a disulfide bond, a thioether bond, a lactam bond or any other bond described herein.

Peptide Dimers In certain embodiments, the present invention includes dimers of any of the monomeric peptide inhibitors described herein or in the accompanying tables, drawings or sequence listings. Also included are dimers of the monomeric peptide inhibitors described herein. These dimers fall within the general term "peptide inhibitor" used herein. An exemplary dimer of the invention is also shown in the attached table, where the dimerized monomeric subunit is shown in square brackets, followed by the linker. Unless otherwise specified, subunits are linked via their C-terminus. The term "dimer", as found in peptide dimers, refers to a compound in which two peptide monomer subunits are linked. The peptide dimer inhibitors of the present invention may contain two identical monomeric subunits that result in a homodimer or may contain two non-identical monomeric subunits that result in a heterodimer. .. The cysteine dimer contains two peptide monomer subunits linked by a disulfide bond between the cysteine residue in one monomer subunit and the cysteine residue in the other monomer subunit.

In some embodiments, the peptide inhibitors of the invention may be active in a dimeric conformation, especially in the presence of free cysteine residues within the peptide. In certain embodiments, it occurs as a synthesized dimer, or dimerizes, especially in the presence of free cysteine monomeric peptides and under oxidative conditions. In some embodiments, the dimer is a homodimer. In other embodiments, the dimer is a heterodimer.

In certain embodiments, the peptide dimer inhibitors of the invention are not limited to this, but herein, for example, in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, Peptide dimer containing two peptide inhibitors of the invention, including a homodimer or heterodimer containing any of the peptide sequences shown in 9, 10, 11, 12, 13, 14 or 15. It is a meter.

Certain amino acid sequences listed in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 have one-letter codes for amino acids. Shown using. However, when only the monomeric peptide inhibitor sequence is shown, in certain embodiments, according to this teaching, and in general, for example, Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, As shown in 8, 9, 10, 11, 12, 13, 14 or 15, these monomeric peptide inhibitors, i.e., monomeric subunits dimerized to peptide dimer inhibitors. Is understood to form.

In certain embodiments, the monomeric subunits of the invention are not limited to, by, but are limited to, a suitable linking moiety, eg, a disulfide bridge between two cysteine residues, one for each peptide monomer subunit. However, it can be dimerized by another suitable linker moiety, including those defined herein. Some of the monomeric subunits have been shown to have C- and N-terminus, both containing free amines. Therefore, to make a peptide dimer inhibitor, the monomer subunit is modified to eliminate either the C-terminal free amine or the N-terminal free amine, thereby freeing the rest. Dimerization with amines can be made possible. In addition, in some cases, the ends of one or more monomeric subunits are trifluoropentyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclo. Acylated organic compounds selected from the group consisting of propyl acetic acid, 4-fluorobenzoic acid, 4-fluorophenyl acetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4carboxylic acid, succinic acid, and glutaric acid are used. Acylate. In some cases, the monomeric subunit contains both a free carboxy terminus and a free amino terminus, whereby the user selectively modifies the subunit to dimer at the desired terminus. Embodying can be achieved. Thus, it will be appreciated by those skilled in the art that the monomeric subunits of the invention can be selectively modified to achieve a single particular amine for the desired dimerization.

Furthermore, it is understood that the C-terminal residue of the monomeric subunit disclosed herein is optionally an amide. Moreover, it has been found that in certain embodiments, dimerization at the C-terminus is facilitated by using suitable amino acids with side chains with amine functionality that are generally understood in the art. Will be done. For N-terminal residues, dimerization can also be achieved through the free amine of the terminal residue, by using the side chain of the appropriate amino acid with the free amine generally understood in the art. It is generally understood that it can also be achieved.

The linker moiety connecting the monomer subunits may include any structure, length, and / or size that fits the teachings herein. In at least one embodiment, the linker moiety is cysteine, lysine, DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, glutaric acid, Isophthalic acid, 1,3-phenylene diacetic acid, 1,4-phenylene diacetic acid, 1,2-phenylene diacetic acid, triazine, Boc-triazine, IDA-biotin, PEG4-biotin, AADA, suitable aliphatic, aromatic , Heteroaromatic, and a non-limiting group consisting of linkers based on polyethylene glycols having a molecular weight of approximately 400 Da to approximately 40,000 Da. A non-limiting example of a suitable linker moiety is presented in Table 2A.

In some embodiments, the peptide dimer inhibitor is dimerized via a linker moiety. In some embodiments, the peptide dimer inhibitor is dimerized via an intermolecular disulfide bond formed between one and two cysteine residues in each monomer subunit. In some embodiments, the peptide dimer inhibitor is dimerized via both the linker moiety and the intermolecular disulfide bond formed between the two cysteine residues. In some embodiments, the intramolecular bond is a thioether, lactam, triazole, selenoether, diselenide or olefin instead of a disulfide bond.

An exemplary diagram of one embodiment of the dimer is shown below:

Those skilled in the art will appreciate that the linker (eg, C-terminal and N-terminal linker) moieties disclosed herein are suitable but non-limiting examples, and that the present invention may include any suitable linker moiety. Will be understood. Accordingly, some embodiments of the invention are selected from peptides comprising or consisting of the sequences shown in any of the tables herein or in any of the tables herein. Contains a homodimer or heterodimer peptide inhibitor composed of two monomer subunits, where the C-terminal or N-terminal (or internal amino acid residue) of each monomer subunit is used. The group) is linked by any suitable linker moiety to provide a dimeric peptide inhibitor having IL-23R inhibitory activity. In certain embodiments, the linker binds to the amino acid residues inside the N-terminus or C-terminus of one monomer subunit and the inside of the other monomer subunit to form a dimer. In certain embodiments, the linker binds to an amino acid residue inside one monomer subunit and an amino acid residue inside the other monomer subunit to form a dimer. In a further embodiment, the linker binds to the N-terminus or C-terminus of both subunits.

In certain embodiments, the peptide inhibitors of the invention comprise two or more polypeptide sequences of the monomeric peptide inhibitors described herein.

In one embodiment, the peptide dimer inhibitors of the invention comprise two peptide monomer subunits linked via one or more linker moieties, each peptide monomer subunit being 7 ~ 35 amino acid residues, 8 ~ 35 amino acid residues, 9 ~ 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acids Residues, 9-25 amino acid residues, 10-25 amino acid residues, 7-20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 7- 18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues containing or consisting of the formulas described herein. Contains the sequence of Ia.

In certain embodiments, one or both of the monomeric subunits comprises a sequence of any one of Formula X, Formula I, II, III, IV or V described herein.

In certain embodiments, the peptide dimer inhibitor comprises two peptide monomer subunits linked via one or more linker moieties, each peptide monomer subunit being 8 to. It is 20 amino acids in length and comprises the sequence of any of the formulas described herein, eg, formula X, formula I, II, III, IV or V. In certain embodiments, the peptide dimer inhibitor comprises two peptide monomer subunits linked via one or more linker moieties, each peptide monomer subunit being 8 to. It is 20 amino acids long and comprises the sequence of any one of formula X, formula I, II, III, IV or V.

In certain embodiments, the peptide dimer inhibitor is of formula VI:

(R ^1- X-R ² ) _2- L (VI)
Has a structure of, or a pharmaceutically acceptable salt or solvent compound thereof,

In the formula, each R ¹ is independently absent or bonded (eg, covalent), or R ¹ is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1- Selected from C6 alkyl, C1 to C20 alkanoyls, including a pegged version alone or as a spacer of either of those described above;

Each R ² is independently absent, bound (eg, covalent), or selected from _{OH or NH 2;}

L is the linker portion;

Each X contains or consists of the sequence of formula Ia described herein, 7-35 amino acid residues, 8-35 amino acid residues, 9-35 amino acids. Residues, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues, 7- 20 amino acid residues, 8-20 amino acid residues, 9-20 amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues A group, or 10 to 18 amino acid residues, each independently selected peptide monomer subunit containing or consisting of amino acid lengths. In certain embodiments, each peptide monomer subunit is a formula Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im described herein. , In, Io, Ip, Iq, Iq', Is, It, IIa, IIb, IIc, IId, IIIa, IIIb, IIIc, IIId, IIIe, IVa, IVb, Va to Vh. ..

In certain embodiments, one or both of the peptide monomer subunits of the peptide dimer inhibitor are cyclized, for example, via an intramolecular bond between X4 and X9. In certain embodiments in which both peptide monomer subunits are cyclized, the intramolecular bond between the two peptide monomer subunits may be the same or different. In certain embodiments, one or both of the intramolecular bonds are disulfide bonds, thioether bonds, lactam bonds, selenoethers, diselenides, or olefin bonds.

In one embodiment, X4 and X9 of one or both of the cyclized peptide monomer subunits are independently selected from Cys, Pen, hCys, D-Pen, D-Cys and D-hCys and are intramolecular. The bond is a disulfide bond.

In one embodiment, one or both X4 and X9 of the cyclized peptide monomer subunit independently represent Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp. , D-Glu and D-Lys, the intramolecular bond is a lactam bond.

In one embodiment, one or both X4 and X9 of the cyclized peptide monomer subunit are independently selected from β-azido-Ala-OH, propargylglycine, and the peptide dimer inhibitor is triazole. It is cyclized through a ring. In one embodiment, X4 and X9 of one or both of the cyclized peptide monomer subunits are independently 2-allylglycine, 2- (3'-butenyl) glycine, 2- (4'-pentenyl), respectively. Selected from glycine, 2- (5'-hexenyl) glycine, the peptide dimer inhibitor is cyclized via ring-closure metathesis to give the corresponding olefin / "staved peptide".

In one embodiment, one or both X4s of the cyclized peptide monomer subunit are 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-Chloro-butyric acid, 3-chloro-isobutyric acid, or hSer (Cl), where one or both X9s of the cyclized peptide monomer subunit are hSer (Cl), Cys, Pen, hCys, D- It is Pen, D-Cys or D-hCys, and the subunit bond is a thioether bond.

In one embodiment, one or both X4s of the cyclized peptide monomer subunit are 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-chloro-propanoic acid, 4-chloro-butyric acid, 3-chloro. -Isobutyric acid, hSer (Cl), or Sec, X9 of one or both of the cyclized peptide monomer subunits is hSer (Cl) or Sec, and the intramolecular bond is a serenoether bond.

In certain embodiments, one or both of the intramolecular bonds are diselenide bonds.

In certain embodiments, one or both of the peptide monomer subunits are linear or non-cyclized.

In certain embodiments of peptide dimer inhibitors, each X7 and each X11 is W. In certain embodiments, each X7 and each X11 is both W, each X10 is Y, and each X4 and X9 are both C. In certain embodiments, each X7 and each X11 is both W, each X10 is Y, and each X4 and X9 is a thioether bond, a lactam bond, a triazole, a serenoether, a diselenide bond, or an olefin. It is an amino acid capable of forming an intramolecular bond that is a bond.

In certain embodiments of peptide dimer inhibitors, one or both of the peptide monomer subunits have, for example, the structures shown herein, or herein. The amino acid sequences shown in, for example, listed in Tables 3A-3I, or peptide dimer inhibitors have the structures shown herein, eg, in Table 3F, or Includes the amino acid sequences shown herein, eg, listed in Table 3F. In certain embodiments, the N-terminus of each subunit comprises a moiety selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl, alone or A pegged version is included as a spacer for any of the above.

In certain embodiments, each ^{R 1} (or N-terminal portion) is independently a bond (e.g., covalent bonds) or is, or hydrogen, C1 -C6 alkyl, C6-C12 aryl, C6-C12 aryl, It is selected from C1-C6 alkyl, C1-C20 alkanoyl, and includes a pegged version as a spacer, either alone or as described above.

In certain embodiments of any of the peptide inhibitors having any of the various formulas described herein, each R ¹ is methyl, acetyl, formyl, benzoyl, trifluoroacetyl, isovaleryl, isobutyryl, It is selected from octanyl and conjugated amides of lauric acid, hexadecanoic acid, and γ-Glu-hexadecanoic acid.

In certain embodiments, each R ² (or C-terminal portion) is independently bonded (eg, covalent) or selected from _{OH or NH 2.}

In any particular embodiment of a peptide inhibitor having any of the various formulas described herein, each X is a 7-35 amino acid residue, an 8-35 amino acid residue, 9-35 amino acid residues, 10-35 amino acid residues, 7-25 amino acid residues, 8-25 amino acid residues, 9-25 amino acid residues, 10-25 amino acid residues Contains or consists of amino acid residues, 7-18 amino acid residues, 8-18 amino acid residues, 9-18 amino acid residues, or 10-18 amino acid residues.

In certain embodiments, one or both Xs comprise or consists of a sequence of any one of the formulas described herein. In certain embodiments of either the dimer or peptide inhibitors, including the formulas described herein, X does not include the amino acid sequence described in US Patent Application Publication No. US2013 / 0029907. Or does not consist of it. In certain embodiments of either the dimer or peptide inhibitors, including the formulas described herein, X does not include the amino acid sequence described in US Patent Application Publication No. US2013 / 0172272. Or does not consist of it.

In certain embodiments of the peptide inhibitors of the invention (both monomeric and dimer) containing Cys at the X4 position and Cys at the X9 position, the Cys at the X4 position and the Cys at the X9 position are disulfide bridged. Are connected by.

In certain embodiments of the peptide inhibitors of the invention, each X7 and each X11 is not necessarily W.

In certain embodiments of the peptide inhibitors of the invention, each X7 and each X11 is W.

In certain embodiments of the peptide inhibitors of the invention, each X7 and each X11 is both W, X10 is Y, and X4 and X9 are both C.

In certain embodiments, at least two cysteine residues of the peptide dimer inhibitor are linked by either intramolecular or intermolecular disulfide bridges.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ix, Ia-It, if allowed), both X4 and X9 are in Cys. is there.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ix, Ia-It, if allowed), both X7 and X11 are in W. is there.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ia-It, if allowed), X7 and X11 are both W. X10 is Y and X4 and X9 are both Cys.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ia-It, if allowed), X15 is Gly or Ser.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ia-It, if allowed), X16 is AEA or AEP.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ia-It, if allowed), the X10 is Tyr or Ph, or Tyr or Phe. Is an analog of.

In certain embodiments of either or both of the monomeric subunits present in the peptide dimer inhibitor (eg, Ia-It, if allowed), X11 is Trp.

In any particular embodiment of a peptide dimer inhibitors described herein, either or both of R ¹ is hydrogen.

In certain embodiments of the peptide dimer inhibitors of the invention, the linker moiety (L) is either the linker described herein or shown in Table 2A or 2B. In certain embodiments, L is a lysine linker, diethylene glycol linker, iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or PEG linker.

In any of the various embodiments of the peptide dimer inhibitor, each of the peptide monomer subunits is attached to the linker moiety via its N-terminus, C-terminus, or internal amino acid residue.

In certain embodiments of any of the peptide dimer inhibitors, a linker moiety is attached to the N-terminus of each peptide monomer subunit.

In certain embodiments of any of the peptide dimer inhibitors, a linker moiety is attached to the C-terminus of each peptide monomer subunit.

In any particular embodiment of the peptide dimer inhibitor, each peptide monomer subunit is linked to a linker moiety attached to an internal amino acid.

In certain embodiments of peptide dimer inhibitors, the linker moiety is a diethylene glycol linker, iminodiacetic acid (IDA) linker, β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or PEG linker. ..

In certain embodiments of peptide dimer inhibitors, either one or both of the peptide monomer subunits has the structure shown in any of the Tables of Examples, or either of the tables of Examples. Contains the amino acid sequence described in.

In certain embodiments of either the dimer or peptide inhibitors, including the formulas described herein, X does not include the amino acid sequence described in US Patent Application Publication No. US2013 / 0029907. , And it doesn't consist of it. In certain embodiments of either the dimer or peptide inhibitors, including the formulas described herein, X does not include the amino acid sequence described in US Patent Application Publication No. US2013 / 0172272. , And it doesn't consist of it.

In certain embodiments of the peptide inhibitors of the invention, each X7 and each X11 is both W, X10 is Y, and both X4 and X9 are Pen.
In certain embodiments, at least two cysteine residues of the peptide dimer inhibitor are linked by either intramolecular or intermolecular disulfide bridges.

Peptide Inhibitor Conjugates and Biopolymers In certain embodiments, the peptide inhibitors of the invention, including both monomers and dimers, are lipophilic, which can be referred to herein as extended half-life portions. Includes one or more conjugated chemical substituents such as substituents and polymer moieties. Although not bound by any particular theory, lipophilic substituents bind to albumin in the bloodstream, thereby shielding the peptide inhibitor from enzymatic degradation and thus its half-life. It is thought to be enhanced. In addition, the polymer moiety is believed to increase half-life and reduce clearance in the bloodstream.

In additional embodiments, the peptide inhibitor, eg, any of the peptides of formulas (Va)-(Vh), further comprises a linker moiety attached to an amino acid residue present within the inhibitor, eg, for example. The linker moiety may be attached to the side chain of any amino acid of the peptide inhibitor, the N-terminal amino acid of the peptide inhibitor, or the C-terminal amino acid of the peptide inhibitor.

In additional embodiments, the peptide inhibitor, eg, any peptide of formulas (Va)-(Vh), further comprises an extended half-life portion attached to an amino acid residue present within the inhibitor, eg, halved. The extended portion may be attached to the side chain of any amino acid of the peptide inhibitor, the N-terminal amino acid of the peptide inhibitor, or the C-terminal amino acid of the peptide inhibitor.

In an additional embodiment, the peptide inhibitor, eg, any peptide of formulas (Va)-(Vh), further adds a half-life extension moiety attached to the linker moiety attached to the amino acid residue present in the inhibitor. Including, for example, the half-life extension portion may be attached to a side chain of any amino acid of the peptide inhibitor, an N-terminal amino acid of the peptide inhibitor, or a linker moiety bound to the C-terminal amino acid of the peptide inhibitor.

（式中、ｎ＝０〜２４またはｎ＝１４〜２４である）
を有する半減期延長部分を含む。 In certain embodiments, the IL23R analog has the structure shown below:

(In the formula, n = 0 to 24 or n = 14 to 24)
Includes a half-life extension portion with.

In certain embodiments, the IL23R analogs of the invention include the half-life extension portion shown in Table 7.

In certain embodiments, the half-life extension is directly attached to the peptide inhibitor, whereas in other embodiments, the half-life extension is shown in a linker moiety, eg, Table 6 or 8. It is bound to a peptide inhibitor via one of them.

In certain embodiments, the peptide inhibitors of the invention are any of the linker moieties shown in Table 8, including any of the following combinations shown in Table 9a, and are shown in Table 7. Includes any of the extended half-life portions that have been made.

In some embodiments, for example, as shown in Table 9b, there may be multiple linkers between the peptide and the conjugate moiety, eg, the half-life extension moiety.

例１：シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１２９０）

例１ａ：Ａｃ−［（Ｄ）−Ａｒｇ］−シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１４１５）

例２：Ａｃ−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（Ａｃ）］−ＮＮ−ＮＨ_２ （配列番号１１８５）

例３：シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）−（リンカー−半減期延長部分）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１４６７）

例３ａ：Ａｃ−［（Ｄ）−Ａｒｇ］シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）−（リンカー−半減期延長部分）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１４６８）

例４：シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＮ−ＮＨ_２ （配列番号１４６９）

例４ａ：Ａｃ−［（Ｄ）−Ａｒｇ］−シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＮ−ＮＨ_２ （配列番号１４７０）

例５：シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＨ_２ （配列番号１４７１）

例５ａ：Ａｃ［（Ｄ）−Ａｒｇ］−シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＨ_２ （配列番号１４７２）

例６：［半減期延長部分−リンカー］−［シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１４７３）

例６ａ：［半減期延長部分−リンカー］−［（Ｄ）−Ａｒｇ］−［シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２ （配列番号１４７４）

例７：［半減期延長部分−リンカー］−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（Ａｃ）］−ＮＮ−ＮＨ_２ （配列番号１４７５）

例８：Ａｃ−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（Ａｃ）］−ＮＮ−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＨ_２ （配列番号１４７６）

例９：Ａｃ−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（アミノエトキシ）−（リンカー−半減期延長部分）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（Ａｃ）］−ＮＮ−ＮＨ_２ （配列番号１４７７）

例１０：Ａｃ−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（リンカー−半減期延長部分）］−ＮＮ−ＮＨ_２ （配列番号１４７８）
Examples of peptide inhibitors of the invention, including those having a conjugated linker and / or an extended half-life portion, are shown below. Unless otherwise specified, all amino acids are L amino acids. The present invention also includes, but is not limited to, the form of salts of any of these peptide inhibitors, including their acetates.

Example 1: Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (sequence) Number 1290)

Example 1a: Ac-[(D) -Arg] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy- Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1415)

Example 2: Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys ( Ac)] -NN-NH ₂ (SEQ ID NO: 1185)

Example 3: Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)-(linker-extended half-life)]-[2-Nal]-[4-amino-4-carboxy-tetrahydro Piran] -ENN-NH ₂ (SEQ ID NO: 1467)

Example 3a: Ac-[(D) -Arg] cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)-(linker-half-life extension portion)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1468)

Example 4: Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (linker-half-life) Period extension part)] -NN-NH ₂ (SEQ ID NO: 1469)

Example 4a: Ac-[(D) -Arg] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy- Tetrahydropyran]-[Lys (linker-extended half-life)]-NN-NH ₂ (SEQ ID NO: 1470)

Example 5: Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN- [Lys (linker) -Half-life extension part)]-NH ₂ (SEQ ID NO: 1471)

Example 5a: Ac [(D) -Arg] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydro Piran] -ENN- [Lys (linker-extended half-life)] -NH ₂ (SEQ ID NO: 1472)

Example 6: [Half-life extension part-linker]-[Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy- Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1473)

Example 6a: [Half-life extension part-linker]-[(D) -Arg]-[Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1474)

Example 7: [Half-life extension part-linker]-[Pen] -NTWQ- [Pen]-[Phe [4- (aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] ]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1475)

Example 8: Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac) ] -NN- [Lys (linker-extended half-life)] -NH ₂ (SEQ ID NO: 1476)

Example 9: Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (aminoethoxy)-(linker-extended half-life)]-[2-Nal]-[4-amino-4-carboxy- Tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1477)

Example 10: Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (linker-linker-) Half-life extension part)] -NN-NH ₂ (SEQ ID NO: 1478)

In certain embodiments, the conjugated chemical substituents, i.e., peptides of the invention that include an extended half-life moiety, have the same half-life but no conjugated chemical substituents. The half-life of the inhibitor is at least 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500%. In certain embodiments, lipophilic substituents and / or polymeric moieties enhance the permeability of the peptide inhibitor through the epithelium and / or its retention in the lamina propria. In certain embodiments, the permeability and / or lamina propria retention of the peptide inhibitors of the invention, including conjugated chemical substituents, through the epithelium is the same but conjugated chemical substituents. The half-life of a non-existent peptide inhibitor is 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500%.

In one embodiment, the side chains of one or more amino acid residues (eg, Lys residues) within the peptide inhibitor of the invention are conjugated (eg, covalently attached) to a lipophilic substituent. .. The lipophilic substituent may be covalently bonded to an atom within the side chain of the amino acid, or may be conjugated to the side chain of the amino acid via one or more spacers. If a spacer is present, it can provide a spacing between the peptide analog and the lipophilic substituent. In certain embodiments, the peptide inhibitor comprises any of the conjugated moieties shown in Tables 2-5.

In certain embodiments, the lipophilic substituent has 4 to 30 C atoms, such as at least 8 or 12 C atoms, preferably 24 or less C atoms, or 20 C atoms. Alternatively, it may contain a hydrocarbon chain having less than that. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety that forms part of the attachment of the amino acid to the side chain or spacer, such as an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. .. In some embodiments, the hydrocarbon chain is substituted with an acyl group, so that the hydrocarbon chain can form part of an alkanoyl group, such as palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

The lipophilic substituent may be conjugated to the side chain of any amino acid in the peptide inhibitor of the invention. In certain embodiments, the side chains of amino acids are carboxy groups, hydroxyl groups, thiol groups, amide groups or amine groups for forming esters, sulfonyl esters, thioesters, amides or sulfonamides with spacers or lipophilic substituents. including. For example, the lipophilic substituent may be conjugated with Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn. In certain embodiments, the lipophilic substituent is conjugated to Lys. When adding a lipophilic substituent, the amino acid designated Lys in any of the formulas provided herein can be replaced, for example, with Dbu, Dpr or Orn.

In certain embodiments, the peptide inhibitors of the invention permeate, for example, by conjugating a chemical moiety with a side chain of one or more amino acids within the peptide, eg, to enhance stability. It can be modified to increase sex or enhance drug-like properties. For example, N (epsilon) of lysine N (epsilon), β-carboxyl of aspartic acid, or γ-carboxyl of glutamic acid can be appropriately functionalized. Therefore, in order to prepare a modified peptide, the amino acids in the peptide can be appropriately modified. In addition, in some cases, the side chains are trifluoropentyl, acetyl, octonyl, butyl, pentyl, hexyl, palmityl, trifluoromethylbutyric acid, cyclopentanecarboxylic acid, cyclopropylacetic acid, 4-fluorobenzoic acid, 4 Acylation is performed with an acylated organic compound selected from the group consisting of -fluorophenylacetic acid, 3-phenylpropionic acid, tetrahydro-2H-pyran-4carboxylic acid, succinic acid, glutaric acid or bile acid. Those skilled in the art will appreciate that a series of conjugates, such as PEG4, isoglu and combinations thereof, can be linked. Those skilled in the art will appreciate that amino acids in peptides can be replaced isosterically, for example Lys with Dap, Dab, α-MeLys or Orn. Examples of modified residues within the peptide are shown in Table 1B.

In a further embodiment of the invention, instead or in addition, the invention is used to increase, for example, solubility and / or half-life and / or bioavailability in vivo (eg, in plasma). The side chain of one or more amino acid residues in the peptide inhibitor of is conjugated to the polymer moiety. It is also known that such modifications reduce the clearance of therapeutic proteins and peptides (eg, renal clearance).

As used herein, "polyethylene glycol" or "PEG" is a polyether compound of the general formula H- (O-CH2-CH2) n-OH. PEGs are also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on their molecular weight. PEO, PEE, or POG, as used herein, refers to an oligomer or polymer of ethylene oxide. Although the three names are chemically synonymous, PEG refers to oligomers and polymers with a molecular weight of less than 20,000 Da, PEO refers to polymers with a molecular weight of more than 20,000 Da, and POE refers to polymers of any molecular weight. Tends to point to. PEG and PEO are liquids or solids with a low melting point, depending on their molecular weight. Throughout this disclosure, the three names are used interchangeably. PEG is prepared by polymerization of ethylene oxide and is commercially available over a wide range of molecular weights from 300 Da to 10,000,000 Da. PEGs and PEOs with different molecular weights are used for different applications and also have different physical properties (eg, viscosities) due to the influence of chain length, and their chemical properties are about the same. The polymer moiety is preferably water soluble (amphipathic or hydrophilic), non-toxic and pharmaceutically inert. Suitable polymer moieties include polyethylene glycol (PEG), homopolymers or copolymers of PEG, monomethyl-substituted polymers of PEG (mPEG), or polyoxyethylene glycerol (POG). For example, Int. J. Hematology Vol. 68: 1 page (1998); Bioconjugate Chem. Volume 6: page 150 (1995); and Crit. Rev. Therap. Drag Carrier Sys. See Volume 9: pp. 249 (1992). Also included are mono-activated, alkoxy-terminated polyalkylene oxides (POAs) such as PEGs prepared for the purpose of prolonging the half-life, such as mono-methoxy-terminated polyethylene glycol (mPEG); bis-activated polyethylene oxide. (Glycol) or other PEG derivatives are also contemplated. Suitable polymers vary substantially in weight and are usually selected from about 200 Da to about 40,000 Da or about 200 Da to about 60,000 Da for the purposes of the present invention. In certain embodiments, PEGs having a molecular weight of 200-2,000 or 200-500 are used. Different forms of PEG can also be used depending on the initiator used in the polymerization process, and common initiators are monofunctional methyl ether PEG, or methoxypoly (ethylene glycol), abbreviated as mPEG.

Low molecular weight PEG is also available as a pure oligomer and is referred to as monodisperse, uniform, or discontinuous. These are used in certain embodiments of the present invention.

PEGs with different geometries are also available: branched PEGs have 3-10 PEG chains emanating from the central core group; stellate PEGs have 10-100 PEG chains emanating from the central core group. The comb-like PEG has multiple PEG chains vertically grafted onto the polymer backbone. The PEG may be linear. The numbers included in the names of PEGs often indicate their average molecular weight (eg, PEGs with n = 9 have an average molecular weight of approximately 400 daltons and are labeled PEG400).

As used herein, "PEGylation" refers to the act of covalently coupling a PEG structure to the peptide inhibitor of the invention, which is then referred to as "PEGylated peptide inhibitor". Is called. In certain embodiments, the PEGylated side chain PEG is a PEG having a molecular weight of about 200 to about 40,000. In some embodiments, the spacers of the peptides of formula I, formula I', or formula I'are pegged. In certain embodiments, the PEG of the PEGylation spacer is PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, or PEG11. In certain embodiments, the PEG of the PEGylation spacer is PEG3 or PEG8.

Other suitable polymeric moieties include poly-amino acids such as poly-lysine, poly-aspartic acid and poly-glutamic acid (eg, Gombotz et al. (1995), Bioconjugate Chem., Vol. 6: pp. 332-351). Hudecz et al. (1992), Bioconjugate Chem., Vol. 3, pp. 49-57 and Tsukada et al. (1984), J. Natl. Cancer Inst., Vol. 73: pp. 721-729). The polymer moiety may be linear or branched. In some embodiments, the molecular weight of the polymer moiety is 500-40,000 Da, for example 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

In some embodiments, the peptide inhibitors of the invention may comprise two or more such polymeric moieties, in which case the total molecular weight of all such moieties is generally presented above. Enter the range.

In some embodiments, the polymer moiety is coupled to an amino, carboxyl or thiol group on the side chain of the amino acid (by covalent linkage). One particular example is the thiol group of the Cys residue and the epsilon amino group of the Lys residue, and the carboxy group of the Asp and Glu residues can also be involved.

Appropriate techniques that can be used to carry out the coupling reaction are well known to those of skill in the art. For example, the PEG moiety having a methoxy group can be coupled to the thiol group of Cys by maleimide linkage using a reagent commercially available from Nektar Therapeutics AL. See also WO2008 / 101017 and the references cited above for more information on suitable chemistry. Maleimide functionalized PEG can also be conjugated to a side chain sulfhydryl group of Cys residues.

Oxidation of disulfide bonds, as used herein, may occur in a single step or is a two-step process. For a single oxidation step, as used herein, trityl protecting groups are often used during assembly, allowing deprotection during cleavage followed by oxidation of the solution. If a second disulfide bond is required, there are native or selective oxidation options. For selective oxidation that requires orthogonal protecting groups, Acm and trityl are used as protecting groups against cysteine. Cleavage removes one protective pair of cysteine, which allows oxidation of this pair. A second oxidative deprotection step of Acm group protected cysteine is then performed. For native oxidation, trityl protecting groups are used for all cysteines, which allows the natural folding of peptides. Appropriate techniques that can be used to carry out the oxidation step will be well understood by those skilled in the art.

Some chemical moieties, including poly (ethylene) glycol, include 20 such as the epsilon amino group of the lysine amino acid residue, the thiol present at the cysteine amino acid residue, or the side chains of other nucleophilic amino acids. Reacts with functional groups found in the naturally occurring amino acids of the species. When multiple naturally occurring amino acids in a peptide inhibitor react, these non-specific chemical reactions are conjugated to one or more poly (ethylene) glycol chains at different positions in the peptide inhibitor. The final peptide inhibitor containing many isomers of the peptide is provided.

One advantage of certain embodiments of the invention is that it has a unique functional group that reacts with activated PEG by chemical properties that are non-reactive with naturally occurring amino acids present in peptide inhibitors. It may be mentioned that one or more chemical moieties (eg, PEG, etc.) can be added by incorporating one or more unnatural amino acids. For example, the azide and alkyne groups are non-reactive with all of the naturally occurring functional groups in the protein. Thus, unnatural amino acids can be incorporated into one or more specific sites in a peptide inhibitor for which PEG or another modification is desired without undesired non-specific reactions. In certain embodiments, certain chemical properties involved in the reaction result in a stable covalent link between the PEG chain and the peptide inhibitor. Moreover, such reactions can be carried out under mild aqueous conditions that do not impair the majority of peptides. In certain embodiments, the non-natural amino acid residue is AHA.

The number and range of chemical moieties attached to natural amino acids is limited. In contrast, with respect to the chemical moieties that attach to non-natural amino acids, the range of useful chemical properties for attaching the available chemical moieties to the target molecule is significantly wider. Any protein (or part thereof) containing an unnatural amino acid containing a reactive site or side chain to which a chemical moiety can be attached, such as an aldehyde derivatized amino acid or a keto derivatized amino acid. Basically any target molecule, including one, can act as a derivative for attaching chemical moieties.

A large number of chemical moieties can be attached or linked to a particular molecule by various methods known in the art. Various such methods are described in US Pat. No. 8,568,706. As an example, the azide moiety can be useful in conjugating chemical moieties such as PEG or others described herein. The azide moiety serves as a reactive functional group and is not present in the majority of naturally occurring compounds (and is therefore non-reactive with the native amino acids of naturally occurring compounds). The azide also undergoes selective ligation with a limited number of reaction partners, and the azide is small and can be introduced into a biological sample without significant changes in molecular size. One reaction that allows the incorporation or introduction of azides into the molecule is the copper-mediated husgen [3 + 2] cycloaddition of azides. This reaction can be used to selectively peg the peptide inhibitor. (Tornoe et al., J. Org. Chem. 67: 3057, 2002; Rostovtsev et al., Angew. Chem., Int. Ed. 41: 596, 2002; and Wang et al., J. Am. Chem. Soc. 125: 3192, 2003, Spacers et al., J. Am. Chem. Soc., 2003, 125, 4686).

Exemplary peptide inhibitors and peptide dimer inhibitors, and methods of producing them. Therefore, the present invention binds or associates with IL-23 to disrupt or block the binding between IL-23 and IL-23R. Various peptide inhibitors are provided.

Exemplary peptide inhibitors and peptide dimer inhibitors of the invention are listed in Tables 3A-3H, 4A, 4B, 5A-5C, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. Shown, the amino acid sequences of the selected monomeric peptide inhibitors and peptide dimer inhibitors are presented, and the linker moieties present within the peptide dimer inhibitors are shown. Multiple peptide inhibitors and peptide dimer inhibitors shown in the accompanying table were synthesized and cyclized according to the protocols discussed herein. Tables E3A-E3H, E4A, E4B, E5A-E5C, E6, E7, E8, E9, E10, E11, E12, E13, E14 or E15 show changes in phosphoSTAT3 levels as described in the accompanying examples. IC50 values for selected monomeric peptide inhibitors and peptide dimer inhibitors in the inhibition of IL-23 binding to IL-23R or the inhibition of IL-23 signaling, as determined by measurement, are presented. Has been done. Illustrative peptide inhibitors of the invention are represented by formula (V) and are also shown in Tables 2-5 where the amino acid sequences of the selected peptide inhibitors are presented. These peptide inhibitors are acetates.

The peptide inhibitors of the present invention can be synthesized by many techniques known to those of skill in the art. In certain embodiments, the techniques described in the accompanying examples are used to synthesize, purify, and dimerize monomeric subunits. In certain embodiments, the present invention is a method of making the peptide inhibitors of the invention (or monomer subunits thereof), including but not limited to formulas I, II, III, IV, V. Alternatively, a peptide comprising, consisting of, or essentially consisting of a peptide having an amino acid sequence described herein, including either VI or any of the amino acid sequences described in the tables herein. A method is provided that includes steps to synthesize. In other embodiments, the peptides are synthesized by recombination instead of chemically synthesizing. In certain embodiments, the peptide inhibitor is a dimer and the method synthesizes both monomeric subunits of the peptide dimer inhibitor, followed by two monomeric subunits. It involves quantifying to produce a peptide dimer inhibitor. In various embodiments, dimerization is achieved by any of the various methods described herein. In certain embodiments, the method of making a peptide inhibitor (or monomeric subunit thereof) further comprises synthesizing the peptide inhibitor (or monomeric subunit thereof) and then cyclizing it. In certain embodiments, cyclization is achieved by any of the various methods described herein. In certain embodiments, the invention is a method of making the peptide inhibitors of the invention (or monomer subunits thereof), but not limited to, Formulas I, II, III, IV, V. Or comprising, consisting of, or essentially a peptide having the amino acid sequence described herein, including any of the amino acid sequences listed in the VI or the accompanying examples, table or sequence listing. Provided is a method comprising the step of introducing an intramolecular bond, such as a disulfide bond, an amide bond, or a thioether bond, between two amino acid residues in the peptide.

In a related embodiment, the invention encodes a polypeptide having a sequence set forth in any one of formulas I, II, III, IV, V or VI or the accompanying Examples, Tables, or Sequence Listings. Contains polynucleotides.

Furthermore, the present invention includes a vector containing the polynucleotide of the present invention, for example, an expression vector.

Treatment Methods In certain embodiments, the invention is a method of inhibiting the binding of IL-23 to IL-23R on cells, comprising contacting IL-23 with a peptide inhibitor of the invention. , Including methods. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. Inhibition of binding can be determined by a variety of conventional experimental methods and assays known in the art.

In certain embodiments, the invention comprises a method of inhibiting IL-23 signaling by a cell, comprising contacting IL-23 with a peptide inhibitor of the invention. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the method is performed in vitro or in vivo. In certain embodiments, inhibition of IL-23 signaling can be determined by measuring changes in phosphoStat3 levels in cells.

In some embodiments, the invention treats a subject suffering from a condition or indication associated with IL-21 or IL-23R (eg, activation of the IL-23 / IL-23R signaling pathway). A method for the like, comprising the step of administering to a subject the peptide inhibitor of the present invention. In one embodiment, it is a method for treating a subject suffering from a condition or indication characterized by inappropriate, deregulated, or increased IL-23 or IL-23R activity or signaling. The method comprises the step of administering to the individual the peptide inhibitor of the present invention in an amount sufficient to inhibit (partially or completely) the binding of IL-23 to IL-23R in the subject. Provided. In certain embodiments, inhibition of the binding of IL-23 to IL-23R is a particular organ or tissue of the subject, such as stomach, small intestine, large intestine / colon, mesentery, lamina propria, Peyer's patches, intestines It occurs in the mesenteric lymph nodes, or in the lymphatic colon.

In some embodiments, the method of the invention comprises providing the peptide inhibitor of the invention to a subject in need thereof. In certain embodiments, it has been determined that the subject in need of it has been diagnosed with or is at risk of developing a disease or disorder associated with IL-23 / IL-23R. In certain embodiments, the subject is a mammal.

In certain embodiments, the disease or disorder is multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), juvenile IBD, adolescent IBD, Crohn's disease, sarcoidosis, systemic elitematodes, ankylosing spondylosis. Autoimmune inflammation such as inflammation (axial spondylotic arthritis), psoriatic arthritis, or psoriasis and related diseases and disorders. In certain embodiments, the disease or disorder is psoriasis (eg, psoriasis vulgaris, guttate psoriasis), inverse psoriasis, pustular psoriasis, palmo-plantar. Psoriasis, psoriasis vulgaris, or psoriatic psoriasis, atopic dermatitis, acne ectopica, ulcerative colitis, Crohn's disease, Celiac's disease Sexual sprue), enteropathy with seronegative arthritis, microscopic colitis, collagen-accumulating colitis, eosinophilia gastroenteritis / esophagitis, colitis associated with radiation or chemotherapy, leukocyte adhesion deficiency-1 Psoriasis with congenital immunity disorders, chronic granulomatosis, glycogenosis type 1b, Hermannsky-Padrac syndrome, Chediac-East syndrome, Wiscot-Aldrich syndrome, rectal colon resection and ileal anastomosis Later ileal psoriasis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mammary psoriasis, psoriasis, bile ductitis, primary biliary cirrhosis, virus-related enteropathy, periductitis, chronic bronchitis, chronic sinusitis, asthma , Psoriasis, or implant-to-host disease.

In certain related embodiments, the present invention selectively inhibits IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in a subject in need thereof. Provided is a method comprising the step of providing a subject with a peptide inhibitor of the present invention. In certain embodiments, the present invention selectively inhibits IL-23 or IL-23R signaling (or binding of IL-23 to IL-23R) in the gastrointestinal tract of a subject in need thereof. A method comprising providing a subject with a peptide inhibitor of the invention by oral administration. In certain embodiments, the exposure of the administered peptide inhibitor in GI tissue (eg, small intestine or colon) is at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold exposure to blood. .. In certain embodiments, the invention is a method of selectively inhibiting IL23 or IL23R signaling (or binding of IL23 to IL23R) in the subject's gastrointestinal tract in need thereof, the peptide to the subject. Includes methods that include providing an inhibitor, wherein the peptide inhibitor does not block the interaction between IL-6 and IL-6R or does not antagonize the IL-12 signaling pathway. In a further related embodiment, the invention is a method of inhibiting GI inflammation and / or neutrophil infiltration into GI, the step of providing a peptide inhibitor of the invention to a subject in need thereof. Including, including methods. In some embodiments, the methods of the invention provide a peptide inhibitor of the invention (ie, a first therapeutic agent) to a subject in need thereof in combination with a second therapeutic agent. Including. In certain embodiments, a second therapeutic agent is provided to the subject prior to and / or simultaneously with and / or after administration of the peptide inhibitor to the subject. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, the second therapeutic agent is a non-steroidal anti-inflammatory drug, steroid, or immunomodulator. In another embodiment, the method comprises administering to the subject a third therapeutic agent. In certain embodiments, the second therapeutic agent is an antibody that binds to IL-23 or IL-23R.

In certain embodiments, the peptide inhibitor, or pharmaceutical composition comprising the peptide inhibitor, is suspended in a sustained release matrix. A sustained release matrix, as used herein, is a matrix made of a material, usually a polymer, that can be degraded by enzyme, acid-base hydrolysis, or dissolution. When inserted into the body, the matrix is affected by enzymes and body fluids. The sustained release matrix includes liposomes, polylactide (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (complex of lactic acid and glycolic acid) polyacid anhydride, poly (ortho) ester, polypeptide, hyaluronic acid. , Collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, and biocompatible materials such as polynucleotides, polyvinylpropylene, polyvinylpyrrolidone and silicones. Is desirable. One embodiment of the biodegradable matrix is one matrix of either polylactide, polyglycolide, or polylactide co-glycolide (copolymer of lactic acid and glycolic acid).

In certain embodiments, the invention comprises a pharmaceutical composition comprising one or more peptide inhibitors of the invention and a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutically acceptable carrier, diluent or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or any type of formulation auxiliary material. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbate and the like. It may also be desirable to include an isotonic agent such as sugar, sodium chloride.

In certain embodiments, the composition is orally, parenterally, in a cistern, intravaginally, intraperitoneally, intrarectally, topically (spray, ointment, drop, suppository). , Or by inhalation (eg, intranasal spray), or by eye (eg, intraocular) or buccal. The term "parenteral" as used herein refers to a form of administration that includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intra-articular injections and infusions. Therefore, in certain embodiments, the composition is formulated for delivery by any of these routes of administration.

In certain embodiments, the pharmaceutical composition for parenteral injection is a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, or sterile injectable immediately prior to use. Includes sterile powder for reconstitution in solution or dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, β-cyclo. Included are injectable organic esters such as dextrin, vegetable oils (eg olive oil, etc.), and ethyl oleate. Reasonable fluidity can be maintained, for example, by using a coating material such as lecithin, by maintaining the required particle size in the case of dispersion, and by using a surfactant. The composition may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Sustained absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

Injectable depot forms include peptide inhibitors in one or more biodegradable polymers, such as polylactide-polyglycolides, poly (orthoesters), poly (acid anhydrides), and (poly) glycols such as PEG. Examples include those produced by forming a microencapsule matrix of. Depending on the peptide-polymer ratio and the nature of the particular polymer used, the rate of release of the peptide inhibitor can be controlled. Depot injection formulations are also prepared by capturing the peptide inhibitor in liposomes or microemulsions that are compatible with body tissue.

Injectable formulations are, for example, by filtering through a bacterial retention filter or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use. Can be sterilized.

Topical administration includes administration to the skin or mucous membranes, including the surface of the lungs and eyes. Compositions for topical pulmonary administration, including those for inhalation and intranasal use, contain solutions and suspensions in aqueous and non-aqueous formulations, and may or may not be pressurized. It can also be prepared as a good dry powder. In the unpressurized powder composition, the active ingredient in finely divided form is mixed with a larger size pharmaceutically acceptable inert carrier containing particles having a size of up to 100 micrometers in diameter, for example. Can be used in. Suitable inert carriers include sugars such as lactose.

Alternatively, the composition may contain a pressurized, compressed gas, such as a nitrogen or liquefied gas atomizer. The liquefied spray medium and in fact the total composition may be such that the active ingredient is not dissolved in it to any substantial extent. The pressurized composition may also contain a surface active agent such as a liquid or solid nonionic surfactant, or may be a solid anionic surface active agent. It is preferred to use a solid anionic surfactant in the form of a sodium salt.

A further form of topical administration is for the eye. The peptide inhibitors of the present invention can be delivered in a pharmaceutically acceptable ophthalmic vehicle, thus providing the peptide inhibitor to the cornea and the area inside the eye, eg, the anterior chamber of the eye. Keep in contact with the surface of the eye for a sufficient period of time to penetrate the posterior chamber, vitreous chamber, aqueous chamber, vitreous fluid, cornea, iris / ciliary body, crystalline body, choroid / retina and strong membrane. Can be done. The pharmaceutically acceptable ophthalmic vehicle may be, for example, an ointment, a vegetable oil or an encapsulating material. Alternatively, the peptide inhibitors of the invention can be injected directly into the vitreous humor and aqueous humor.

Compositions for rectal or vaginal administration include suppositories, which melt the peptide inhibitors of the invention solid at room temperature but liquid at body temperature and thus in the rectal or vaginal cavity. It can be prepared by mixing with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which releases the active compound.

The peptide inhibitors of the invention can also be administered on liposomes or other lipid-based carriers. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any NOAEL, physiologically acceptable and metabolizable lipid capable of forming ribosomes can be used. The composition in the form of liposomes may contain stabilizers, preservatives, excipients and the like in addition to the peptide inhibitors of the present invention. In certain embodiments, the lipid comprises a phospholipid, both natural and synthetic, including phosphatidylcholine (lecithin) and serine. Methods for forming liposomes are known in the art.

Pharmaceutical compositions suitable for parenteral administration used in the present invention generally include sterile aqueous solutions of peptide inhibitors made isotonic with the recipient's blood using sodium chloride, glycerin, glucose, mannitol, sorbitol and /. Alternatively, it may contain a suspension or the like.

In some embodiments, the invention provides a pharmaceutical composition for oral delivery. The compositions and peptide inhibitors of the invention can be prepared for oral administration according to any of the methods, techniques, and / or delivery vehicles described herein. Further, the peptide inhibitors of the present invention, which are not disclosed herein, are well known in the art and can be modified or incorporated into a system or delivery vehicle suitable for use in oral delivery of peptides. Those skilled in the art will understand that they can.

In certain embodiments, the formulation for oral administration is a non-assistant for artificially increasing the permeability of the intestinal wall, such as resorcinol and / or polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. Ionic surfactants) and / or enzyme inhibitors for inhibiting enzymatic degradation (eg, pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or tragyrol) may be included. In certain embodiments, solid-type dosage form peptide inhibitors for oral administration include sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, It can be mixed with at least one additive such as pectin, tragacant gum, arabic gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. These dosage forms are other types of additives (s), such as inert diluting agents, lubricants such as magnesium stearate, preserving agents such as parabens, sorbic acid, ascorbic acid, alpha tocopherols. It may also contain antioxidants such as agents, cysteines, disintegrants, binders, thickeners, buffers, pH regulators, sweeteners, flavoring agents or perfuming agents.

In certain embodiments, an oral dosage form or unit dose suitable for use with the peptide inhibitors of the invention is considered to be a mixture of peptide inhibitors and non-drug components or excipients, as well as either ingredients or packaging. Other non-reusable materials that can be included may be included. The oral composition may include at least one of a liquid dosage form, a solid dosage form, and a semi-solid dosage form. In some embodiments, oral dosage forms containing effective amounts of peptide inhibitors are provided, the dosage forms of pills, tablets, capsules, gels, pastes, beverages, syrups, ointments, and suppositories. Contains at least one of the agents. In some cases, oral dosage forms designed and configured to achieve delayed release of the peptide inhibitor in the subject's small intestine and / or colon are provided.

In one embodiment, an oral pharmaceutical composition comprising a peptide inhibitor of the invention comprises an enteric coating designed to delay the release of the peptide inhibitor in the small intestine. In at least some embodiments, a pharmaceutical composition comprising the peptide inhibitor of the present invention and a protease inhibitor such as aprotinin in a delayed release pharmaceutical formulation is provided. In some cases, the pharmaceutical compositions of the present invention comprise an enteric coating that is soluble in gastric juice with a pH of about 5.0 or higher. In at least one embodiment, polymers with dissociable carboxy groups, such as cellulose derivatives, including hydroxypropylmethyl cellulose phthalate, cellulose phthalate acetate and cellulose trimellitic acetate and similar cellulose derivatives, and other carbohydrate polymers. Provided is a pharmaceutical composition comprising an enteric coating comprising.

In one embodiment, a pharmaceutical composition comprising a peptide inhibitor of the invention is provided in an enteric coating, which protects the pharmaceutical composition in a controlled manner within the subject's lower gastrointestinal system. And to release, and further to avoid systemic side effects. In addition to enteric coatings, the peptide inhibitors of the invention can be encapsulated, coated, fitted, or otherwise associated within any compatible oral drug delivery system or component. .. For example, in some embodiments, the peptide inhibitors of the invention are provided in lipid carrier systems that include at least one of a polymer hydrogel, nanoparticles, microspheres, micelles, and other lipid systems.

To overcome peptide degradation in the small intestine, some embodiments of the invention include a hydrogel polymer carrier system containing the peptide inhibitors of the invention, whereby the hydrogel polymer causes the peptide inhibitors to be in the small intestine and / or. Or protected from proteolysis in the small intestine. The peptide inhibitors of the present invention can be further formulated for use with carrier systems designed to increase lytic kinetics and enhance intestinal absorption of peptides. These methods include the use of liposomes, micelles and nanoparticles to increase gastrointestinal permeation of peptides.

Various bioresponsive systems can also be combined with one or more peptide inhibitors of the invention to provide pharmaceuticals for oral delivery. In some embodiments, the peptide inhibitors of the invention are hydrogels with hydrogen bonding groups and mucosal adhesive polymers such as PEG, poly (methacrylic acid) acid [PMAA], cellulose, Eudragit®, chitosan and Used in combination with a bioresponsive system such as alginate) to provide a therapeutic agent for oral administration. Other embodiments include methods of optimizing or prolonging the drug residence time of peptide inhibitors disclosed herein, where the surface of the peptide inhibitor is hydrogen bonded, linked to a mucin, or a polymer or / And modified to include mucosal adhesion through hydrophobic interactions. These modified peptide molecules can be demonstrated to increase drug residence time in a subject depending on the desired characteristics of the invention. In addition, the targeted mucosal adhesion system can specifically bind to receptors on enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing peptide inhibitors.

Another embodiment is a method for oral delivery of the peptide inhibitors of the invention, which facilitate the transport of peptides across the intestinal mucosa by increasing paracellular or transcellular permeation. Includes methods of providing to a subject in combination with an enhancer. Various permeation enhancers and methods for oral delivery of therapeutic agents are described in Braiden, D. et al. J. , Mrsny, R.M. J. , 2011, Oral peptide delivery: prioritizing the leading technologies. The. Delivery, Vol. 2, (No. 12), pp. 1567-1573.

In certain embodiments, the pharmaceutical compositions and formulations of the invention include the peptide inhibitors of the invention and one or more permeation enhancers. Examples of absorption enhancers include, for example, bile salts, fatty acids, surfactant (anionic, cationic, and nonionic) chelating agents, Zonular OT, esters, cyclodextrins, dextran sulfates, azones, crowns. Examples include ether, EDTA, sucrose ester, and phosphatidyl choline. Absorption enhancers are generally not carriers on their own, but have also been extensively associated with other carriers to improve their oral bioavailability by transporting peptides and proteins across the intestinal mucosa. Such substances can be added to the formulation as excipients or incorporated to form a non-specific interaction with the intended peptide inhibitor.

Dietary components and / or other naturally occurring substances that have been identified as enhanced permeation of tight junctions and as Generally Recognized As Safe (GRAS) include, for example, glycerides, acylcarnitines, and the like. Bile salts, and medium-chain fatty acids are included. The sodium salt of medium chain fatty acid (MCFAS) has also been suggested as a permeation enhancer. The most extensively tested MCFAS is sodium capricate, a salt of capric acid, which contains 2-3% fatty acids in the milk fat fraction. To date, sodium caprinate has been used primarily as an excipient in suppository formulations (Doctallin ™) to improve ampicillin absorption in the rectum. Another dietary MCFAS, sodium caprylate (8 carbons), has been shown to have lower permeation properties in vitro compared to sodium caprate. Sodium caprylate and the peptidic drug were formulated as a mixture with other excipients in the oil to produce an oily suspension (OS) that enhances permeability (Tuvia, S. et al., Et al. Pharmaceutical Research, Vol. 31, No. 8, pp. 2010-2021 (2014).

For example, in one embodiment, the permeation enhancer is combined with a peptide inhibitor, which comprises at least one of a medium chain fatty acid, a long chain fatty acid, a bile acid salt, an amphipathic surfactant, and a chelating agent. Including. In certain embodiments, medium chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. In one embodiment, a permeation enhancer containing N- [hydroxybenzoyl) amino] sodium caprylate is used to form a weak non-covalent association with the peptide inhibitor of the invention, where the permeabilizer is It is advantageous for membrane transport and further dissociates when it reaches the blood circulation. In another embodiment, the peptide inhibitors of the invention are conjugated to oligoarginine, thereby increasing cell penetration of the peptide into various cell types. In addition, in at least one embodiment, a non-covalent bond is imparted between the peptide inhibitor of the invention and a permeation enhancer selected from the group consisting of cyclodextrin (CD) and dendrimers, wherein the non-covalent bond is hereby. Permeation enhancers reduce peptide aggregation and increase the stability and solubility of peptide inhibitor molecules.

In certain embodiments, the pharmaceutical composition or formulation comprises a peptide inhibitor of the invention and a transient permeation enhancer (TPE). Permeation enhancers and TPEs can be used to increase oral bioavailability or peptide inhibitors. One example of a TPE that can be used is an oily suspension that disperses a powder containing sodium caprylate and a therapeutic agent (Tuvia, S. et al., Pharmaceutical Research, Vol. 31, No. 8, 2010-2021). Page (2014).

In certain embodiments, the pharmaceutical compositions and formulations may comprise the peptide inhibitors of the invention and one or more absorption enhancers, enzyme inhibitors, or mucosal adhesive polymers.

In certain embodiments, the peptide inhibitors of the invention are formulated in a formulation vehicle, such as an emulsion, liposome, microspheres or nanoparticles.

Other embodiments of the invention provide a method for treating a subject with a peptide inhibitor of the invention with an increased half-life. In one aspect, the invention is administered in vitro or in vivo (eg, to a human subject) sufficient to administer a therapeutically effective amount daily (q.d.) or twice daily (bi.d.). Provided is a peptide inhibitor having a half-life of at least several hours to 1 day. In another embodiment, the peptide inhibitor has a half-life of 3 days or longer, sufficient to administer a therapeutically effective amount weekly (qw). In addition, in another embodiment, the peptide inhibitor has a half-life of 8 days or longer, sufficient to administer a therapeutically effective amount biweekly (biw) or monthly. In another embodiment, the peptide inhibitor is derivatized or modified so that it has a longer half-life compared to an underivatized or unmodified peptide inhibitor. In another embodiment, the peptide inhibitor contains one or more chemical modifications to increase the serum half-life.

When used in at least one of the treatments or delivery systems described herein, the peptide inhibitors of the invention are such in pure form or in the presence of pharmaceutically acceptable salt forms. Can be used in form.

The total daily usage of the peptide inhibitors and compositions of the present invention can be determined by the attending physician within the scope of sound medical judgment. The level of a particular therapeutically effective dose for any particular subject depends on a variety of factors, including: a) the disorder being treated and the severity of the disorder; b) the activity of the particular compound used. C) Specific composition used, patient age, weight, overall health, gender and diet; d) Time of administration, route of administration, and rate of excretion of the specific peptide inhibitor used; e) Treatment Duration of; f) Drugs used in combination with or at the same time as the particular peptide inhibitor used, as well as factors well known in the medical arts.

In certain embodiments, the total daily dose of the peptide inhibitor of the invention administered to a human or other mammalian host in single or divided doses is, for example, from 0.0001 mg / kg body weight daily. The amount may be up to 300 mg, or daily, from 1 mg to 300 mg per kg body weight.

Non-Invasive Detection of Intestinal Inflammation The peptide inhibitors of the present invention can be used to detect, evaluate and diagnose intestinal inflammation by microPET imaging, where, as part of a non-invasive diagnostic procedure. Label the peptide inhibitor with a chelating group or a detectable label. In one embodiment, the peptide inhibitor is conjugated with a bifunctional chelating agent. In another embodiment, the peptide inhibitor is radiolabeled. The labeled peptide inhibitor is then administered orally or rectally to the subject. In one embodiment, the labeled peptide inhibitor is included in the drinking water. After uptake of the peptide inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestine and gastrointestinal tract.

Identification of Peptide Inhibitors that Inhibit IL-23 Signal Transduction As described herein, in certain embodiments, the peptide inhibitors of the invention are human IL-23R and compared to mouse IL-23R. / Or preferentially binds to rat IL-23R. The mouse IL-23R is an amino acid additional to the region corresponding to approximately amino acid residues 315 to approximately amino acid residues 340 of the mouse IL23R protein, eg, the amino acid region NWQPWSSPFVHQTSQETGKR, as compared to human IL-23R or rat IL-23R. (See, for example, FIG. 4). In certain embodiments, the peptide inhibitor binds to the region of human IL-23R from approximately amino acid 230 to approximately amino acid residue 370.

The present invention is based on identifying agents (eg, peptides) that preferentially bind to human IL-23R or rat IL-23R as compared to mouse IL-23R, and inhibitors of IL-23R (eg, peptides). Inhibitors) provide new methods for identifying. In certain embodiments, the method is (a) determining the amount of binding of the candidate agent to a human IL-23R polypeptide or rat IL-23R polypeptide; (b) a mouse IL-23R poly of the candidate agent. Steps to determine the amount of binding to the peptide; and (c) the determined amount of binding to the human IL-23R or rat IL-23R polypeptide and the determined binding to the mouse IL-23R polypeptide. If the amount of binding to the determined human IL-23R or rat IL-23R polypeptide is greater than the amount of binding to the mouse IL-23R polypeptide, including the step of comparing the amounts of the candidate compound. Is an inhibitor of IL-23R. In certain embodiments, the candidate compound has a determined amount of binding to a human IL-23R polypeptide or rat IL-23R polypeptide that is at least one of the determined amount of binding to a mouse IL-23R polypeptide. .5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times, at least 500 If it is double, or at least 100-fold, it is identified as an inhibitor of IL-23R. In certain embodiments, the candidate compound is a peptide. In certain embodiments, the peptide is one of the formulas described herein. In certain embodiments, the human IL-23 polypeptide or rat IL-23R polypeptide comprises or consists of a full-length human IL-23R or rat IL-23R protein, respectively. In another embodiment, the human IL-23R polypeptide comprises eight or more amino acid residues within the region from approximately amino acid residues 230 to approximately amino acid residues 370 of human IL-23R, the full length human IL. It is a fragment of -23R protein. In another embodiment, the rat IL-23R polypeptide comprises eight or more amino acid residues within the region from approximately amino acid residues 245 to approximately amino acid residues 385 of rat IL-23R, full-length rat IL. It is a fragment of -23R protein.

In another embodiment, the invention refers to additional amino acids from approximately amino acid residues 315 to approximately amino acid residues 340 of the mouse IL23R protein in mouse IL-23R, such as the amino acid region NWQPWSSPFVHQTSQETGKR (see, eg, FIG. 4). Identify IL-23R inhibitors (eg, peptide inhibitors) based on identifying agents that bind to regions of human IL-23R or rat IL-23 that are disturbed by the presence of protein. Providing a new way for. In certain embodiments, the method is (a) a fragment of a human IL-23R polypeptide that falls within the range of approximately 230 to approximately 370 amino acid residues of the candidate agent, or approximately from approximately amino acid residue 245. Steps to determine the amount of binding of a rat IL-23R polypeptide that falls within the range of amino acid residues 385; (b) What is a negative control of a candidate drug (eg, human IL-23R or rat-IL-23R? Steps to Determine the Amount of Binding to (Unrelated Negative Control Peptide); (c) The amount of binding to the determined human IL-23R polypeptide fragment or rat IL-23R polypeptide fragment and the determined negative If the amount of binding to the determined human IL-23R polypeptide fragment or rat IL-23R polypeptide fragment is greater than the amount of binding to the negative control, it comprises the step of comparing the amount of binding to the control. The candidate compound is an inhibitor of IL-23R. In certain embodiments, the candidate compound has a determined amount of binding to a human IL-23R polypeptide fragment or rat IL-23R polypeptide fragment of at least 1.5 of the amount of binding to a determined negative control. Double, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, Or at least 100-fold, it is identified as an inhibitor of IL-23R. In certain embodiments, the candidate compound is a peptide. In certain embodiments, the peptide is one of the formulas described herein. In certain embodiments, the fragments of human IL-23R are at least 8, at least 12, at least 20, and at least 50 within the region of approximately amino acid residues 230 to approximately amino acid residues 370 of human IL-23R. , Or at least 100, or all amino acid residues. In other embodiments, fragments of the rat IL-23R polypeptide are at least 8, at least 12, at least 20, at least 8, within the region from approximately amino acid residues 245 to approximately amino acid residues 385 of rat IL-23R. Contains 50, or at least 100, or all amino acid residues.

Methods of determining binding of a candidate compound to an IL-23 polypeptide are known in the art and are limited to, but are not limited to, in vitro and cell-based binding, including those described herein. Assays can be mentioned. For example, the labeled candidate compound is incubated with a recombinantly prepared IL-23R polypeptide or negative control bound to a solid support under conditions sufficient to allow binding for a sufficient period of time. The binding can then be determined by measuring the amount of label associated with the bound IL-23R polypeptide.

Non-Invasive Detection of Intestinal Inflammation The peptide inhibitors of the present invention can be used to detect, evaluate and diagnose intestinal inflammation by microPET imaging, where, as part of a non-invasive diagnostic procedure. Label the peptide inhibitor with a chelating group or a detectable label. In one embodiment, the peptide inhibitor is conjugated with a bifunctional chelating agent. In another embodiment, the peptide inhibitor is radiolabeled. The labeled peptide inhibitor is then administered orally or rectally to the subject. In one embodiment, the labeled peptide inhibitor is included in the drinking water. After uptake of the peptide inhibitor, microPET imaging can be used to visualize inflammation throughout the subject's intestine and gastrointestinal tract.

Animal Models of IBD The present invention includes models of inflammatory bowel diseases, including inflammatory diseases and disorders such as Crohn's disease and colitis. Several animal models of inflammatory diseases and disorders have been developed as described in the accompanying examples.

In one embodiment, the invention is a method of assessing the ability of a candidate compound to inhibit or alleviate an inflammatory disease disorder.

(A) A step of providing rats with a sufficient amount of sodium dextran sulfate (DSS) to induce IBD;

(B) A step of providing a predetermined amount of a candidate compound to a rat;

(C) Including the step of measuring the amount of IBD symptoms present in the rat after providing the DSS and candidate compounds

The amount of IBD symptoms measured in (c) is the amount measured in a control rat (eg, vehicle control) that is provided with a predetermined amount of DSS and is provided with a predetermined amount of control compound or no peptide. If significantly less than, the candidate compound comprises a method of inhibiting or ameliorating an inflammatory disease or disorder.

In certain embodiments, rats are provided with DSS for about 5-12 days, eg, about 9 days. In certain embodiments, the rats are DSSed by freely exposing the rat to drinking water containing DSS, eg, about 1% to about 10% DSS, about 2% to about 5% DSS, or about 3% DSS. I will provide a. In certain embodiments, rats are provided with the test compound at about 5 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, or about 20 mg / kg or about 30 mg / kg. In certain embodiments, the test compound is provided to the rat orally, eg, in drinking water. In certain embodiments, the DSS assay is performed as described in the accompanying examples.

In another embodiment, the invention is a method of assessing the ability of a candidate compound to inhibit or alleviate an inflammatory disease disorder.

(A) A step of providing rats with a sufficient amount of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce IBD;

(B) A step of providing a predetermined amount of a candidate compound to a rat;

(C) Including the step of measuring the amount of IBD symptoms present in rats after providing TNBS and candidate compounds.

The amount of IBD symptoms measured in (c) is the amount measured in a control rat (eg, vehicle control) that is provided with a predetermined amount of TNBS and is provided with a predetermined amount of control compound or no peptide. Includes methods by which the candidate compound inhibits or alleviates an inflammatory disease or disorder, if significantly less than.

In certain embodiments, the animal has about 10 mg / kg to about 200 mg / kg of TNBS, such as about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg. TNBS of about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 120 mg / kg, about 150 mg / kg or about 200 mg / kg are provided. In certain embodiments, the TNBS is in alcohol, eg, 45% -50% ethanol. In certain embodiments, the TNBS is administered intrarectally. In certain embodiments, rats are provided with the test compound at about 5 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg, or about 20 mg / kg or about 30 mg / kg. In certain embodiments, the test compound is provided to the rat orally, eg, in drinking water. In certain embodiments, the TNBS assay is performed as described in the accompanying examples.

In certain embodiments, immediately after providing the DSS or TNBS and the candidate compound (or no test compound or compound), or after first providing the DSS or TNBS and the candidate compound (or no test compound or compound), for example, about. IBD symptoms are measured after 3, 5, or 9 days. In certain embodiments, the IBD symptoms measured include one or more of percent weight loss, stool consistency, quantitative hemocult score, and colon weight: colon length ratio. In certain embodiments, IBD symptoms are measured using a disease activity index (DAI) score and / or colon weight: colon length ratio, and the DAI score is a percentage weight loss. , Stool consistency, and a score from three parameters, including a quantitative hemocult score, and a maximum of three units can be achieved.

In certain embodiments, the neutralizing anti-IL-23p19 antibody is used as a comparator or positive control.

In certain embodiments, animals are observed daily for clinical signs, including, for example, percent weight loss and signs of loose stools or diarrhea, to assess the extent of the inflammatory response. After a period after inoculation of DSS or TNBS (eg, 5 days, 6 days, or 7 days), the rats are sacrificed and their total colon length from cecum to rectum and colon weight are recorded. The severity of colitis can be assessed by a pathologist who is blinded to the identity of the procedure. In addition to colon wall thickness, macroscopic colonic damage could be assessed on a 0-4 scale according to Table 19 below, and histopathological scores were determined based on the following parameters () Tables 20 and 21).

In certain embodiments, IBD symptoms are measured in three rat groups, each with at least three animals, eg, six animals each, and the three groups are vehicle, DSS or TNBS, and positive controls ( For example, sulfasalazine comprises DSS or TNBS with 100 mg / kg PO, QD).

(Example 1)
Synthesis of Peptide Monomers The peptide monomers of the present invention were synthesized using the Merrifield solid-phase synthesis technique in the Symphony multi-channel synthesizer of Protein Technology. Peptides were assembled using HBTU (O-benzotriazole-N, N, N', N'-tetramethyl-uronium-hexafluoro-phosphate), diisopropylethylamine (DIEA) coupling conditions. For some amino acid couplings, PyAOP (7-azabenzotriazole-1-yloxy) tripyrrolidinophosponium hexafluorophosphate) and DIEA conditions were used. Ring Amid MBHA resin (100-200 mesh, 0.57 mmol / g) was used for peptides with C-terminal amides, and Wang Resin was preloaded with N-α-Fmoc protected amino acids for peptides with C-terminal acids. It was used. Coupling reagents (premixed HBTU and DIEA) were prepared to a concentration of 100 mmol. Similarly, an amino acid solution was prepared to a concentration of 100 mmol. The peptide inhibitors of the invention were identified and screened based on medical chemical optimization and / or phage display to identify those with excellent binding and / or inhibitory properties.

Assembly The peptides were assembled using the standard Symphony protocol. The peptide sequences were assembled as follows: The resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4 ml DMF, followed by 2.5 ml of 20% 4-methylpiperidine (Fmoc deprotection). Was treated for 10 minutes. The resin was then filtered, washed twice with DMF (4 ml) and reprocessed with N-methylpiperidine for an additional 30 minutes. The resin was washed again with DMF (4 ml) three times, after which 2.5 ml of amino acids and 2.5 ml of the HBTU-DIEA mixture were added. After frequent stirring over 45 minutes, the resin was filtered and washed 3 times with DMF (4 ml each). Double coupling was performed on typical peptides of the invention. After the coupling reaction was completed, the resin was washed 3 times with DMF (4 ml each) before proceeding to the next amino acid coupling.

Ring-closing metathesis resin (100 μmol) for forming olefins was washed with 2 ml DCM (3 x 1 min), then with 2 ml DCE (3 x 1 min), followed by a 1st generation Grubbs catalyst in DCE. Treatment was performed with 2 ml of a 6 mM solution (4.94 mg / ml; 20 mol% for resin substitution). The solution was refluxed under nitrogen overnight (12 hours) and then drained. The resin was washed 3 times with DMF (4 ml each), washed with DCM (4 ml), then dried and cleaved.

Cleavage After the peptide assembly is complete, such as Reagent K (82.5% trifluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol), etc. The peptide was cleaved from the resin by treatment with a cleaving reagent. The cleaving reagent allowed the peptide to be successfully cleaved from the resin and all remaining side chain protecting groups.

The cleaved peptide was precipitated in cold diethyl ether and then washed twice with ethyl ether. The filtrate was poured out, a second aliquot of cold ether was added and this procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile: water (with 7: 3, 1% TFA) and filtered. The quality of the linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass / Waters ZQ) and then purified.

Disulfide bond formation by oxidation Peptides containing free thiols (eg, diPen) were assembled on the Link Amide-MBHA resin according to common Fmoc-SPPS procedures. The peptide was cleaved from the resin by treatment with a cleaving reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether and then washed twice with ethyl ether. The filtrate was poured out, a second aliquot of cold ether was added and this procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile: water (with 7: 3, 1% TFA) and filtered to give the desired crude peptide of unoxidized peptide.

A crude cleaved peptide in which X4 and X9 had either Cys, Pen, hCys, (D) Pen, (D) Cys or (D) hCys was dissolved in 20 ml of water: acetonitrile. Then, saturated iodine in acetic acid was added dropwise with stirring until the yellow color persisted. The solution was stirred for 15 minutes and the reaction was monitored by analytical HPLC and LCMS. When the reaction was complete, solid ascorbic acid was added until the solution was clear. The solvent mixture is then first diluted with water and then loaded into a reverse phase HPLC machine (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B). Purified by acetonitrile (ACN) containing 0.1% TFA, at a flow rate of 15 ml per minute, starting with a gradient of 5% B and changing to 50% B over 60 minutes. The fraction containing the pure product was then lyophilized in a lyophilizer.

Lactam Bond Formation 100 mg (approximately 0.12 mmol) of crude cleaved peptide is dissolved in 100 ml of anhydrous dichloromethane. HOBt (1-hydroxybenzotriazole hydrate) (0.24 mmol, 2 eq) was added, followed by DIEA (N, N-diisopropylethylamine) (1.2 mmol, 10 eq) and TBTU (O- (benzotriazole). -1-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate) (0.24 mmol, 2 eq) is added. The mixture is stirred overnight and the reaction is followed by HPLC. When the reaction is complete, dichloromethane is evaporated, diluted with water and acetonitrile, and then loaded into a reverse phase HPLC machine (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA. , Mobile phase B: acetonitrile (ACN) containing 0.1% TFA, at a flow rate of 15 ml / min, the gradient starts at 5% B and changes to 50% B over 60 minutes). The fraction containing the pure product is then lyophilized in a lyophilizer.

Triazole bond formation Purified peptides containing the associated amino acids alkynes and azides were stirred in phosphate / MeOH (2: 1), pH 7.4 (1 mg / 2 ml) at room temperature. CuSO4.5H ₂ O (10 eq) and sodium ascorbate (10 eq) were added and the mixture was stirred at room temperature for 36 hours. MeOH was removed and the solution was acidified to pH 3 with a 1% TFA water mixture. The solution was then filtered and then loaded onto HPLC for peptide purification.

Thioether bond formation Peptides containing free thiols (eg Cys) and hSer (OTBDMS) were assembled on the Link Amide-MBHA resin according to common Fmoc-SPPS procedures. _{The resin was chlorinated in DCM by treatment with PPh 3} (10 eq) and Cl ₃ CCN (10 eq) for 2 hours. The peptide was cleaved from the resin by treatment with a cleaving reagent (90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptide was precipitated in cold diethyl ether and then washed twice with ethyl ether. The filtrate was poured out, a second aliquot of cold ether was added and this procedure was repeated. The crude peptide was dissolved in a solution of acetonitrile: water (with 7: 3, 1% TFA) and filtered to give the desired uncyclized crude peptide.

Free thiols at either the X4 and X9 positions or the X9 and X4 positions (eg Cys, Pen, hCys, (D) Pen, (D) Cys or (D) hCys) and alkyl halides (hSer (Cl)). ) Was dissolved in 0.1 M Tris buffer, pH 8.5. It was cyclized overnight at room temperature. The solvent mixture is then first diluted 2-fold with water and then loaded into a reverse phase HPLC machine (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, transfer. Phase B: acetonitrile (ACN) containing 0.1% TFA, at a flow rate of 15 ml / min, starting with a gradient of 5% B and changing to 50% B over 60 minutes). The fraction containing the pure product was then lyophilized in a lyophilizer.

Serenoether bond formation A crude peptide containing a thiol-protected selenium amino acid and an alkyl halide in X4 and X9 was dissolved in 0.1 M sodium phosphate buffer, pH 5.5, containing DTT (40 eq). It was cyclized at room temperature for 24 hours. The solution was then diluted 2-fold with water and the final cyclized peptide was purified using RP-HPLC to give selenoether.

Diselenide bond formation The diselenide precursor was dissolved in a solution of isopropanol containing 0.1 M phosphate buffer, pH 6.0 and DTT (40 eq) and the reaction mixture was incubated at 37 ° C. After 20 hours, additional DTT (10 eq) was added to the reactants. After a total of 32 hours, the cyclization reaction was then diluted 2-fold with water and the final cyclized peptide was purified using RP-HPLC to give diselenide.

Purification Analytical Reverse Phase High Performance Liquid Chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm x 250 mm) (Phenomenex). Half-reverse phase HPLC was performed on a Gemini 10 μm C18 column (22 mm × 250 mm) (Phenomenex) or a Jupiter 10 μm, 300 A ° C18 column (21.2 mm × 250 mm) (Phenomenex). Linear gradient of B in buffer A at flow rates of 1 mL (analysis) per minute (analysis) and 15 mL (preparation) per minute (mobile phase A: water containing 0.15% TFA, mobile phase B: 0.1% Separation was achieved using acetonitrile (ACN) containing TFA. Linear gradient of B in buffer A at flow rates of 1 mL (analysis) per minute (analysis) and 15 mL (preparation) per minute (mobile phase A: water containing 0.15% TFA, mobile phase B: 0.1% Separation was achieved using acetonitrile (ACN) containing TFA.

Linker activation and dimerization Peptide monomer subunits were linked to form a peptide dimer inhibitor as described below.

Small DIG Linker Activation Procedure: A glass containing 5 mL of NMP containing IDA diacid (304.2 mg, 1 mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 eq, 2.2 mmol) and a stir bar. Added to the vial. The mixture was stirred at room temperature to completely dissolve the solid starting material. N, N'-dicyclohexylcarbodiimide (DCC, 453.9 mg, 2.2 eq, 2.2 mmol) was then added to the mixture. Precipitation was seen within 10 minutes and the reaction mixture was further stirred at room temperature overnight. The reaction mixture was then filtered to remove the precipitated dicyclohexylurea (DCU). Activated linkers were maintained in closed vials prior to use for dimerization. The nominal concentration of activated linker was approximately 0.20 M.

No preactivation step was involved for dimerization using the PEG linker. A commercially available pre-activated bifunctional PEG linker was used.

Dimerization procedure: 2 mL of anhydrous DMF was added to the vial containing the peptide monomer (0.1 mmol). The pH of the peptide was adjusted to 8-9 using DIEA. The activated linker (IDA or PEG13, PEG25) (0.48 eq, 0.048 mmol relative to the monomer) was then added to the monomer solution. The reaction mixture was stirred at room temperature for 1 hour. Completion of the dimerization reaction was monitored using analytical HPLC. The time required to complete the dimerization reaction varied depending on the linker. After the reaction was complete, the peptides were precipitated in cold ether and centrifuged. The supernatant ether layer was discarded. The precipitation step was repeated twice. The crude dimer was then subjected to reverse phase HPLC (Luna C18 support, 10u, 100A, mobile phase A: water containing 0.1% TFA, mobile phase B: acetonitrile containing 0.1% TFA (Luna C18 support, 10u, 100A). ACN), purified using a flow rate of 15 ml / min, gradient changing to 15% B and 45% B over 60 minutes). The fraction containing the pure product was then lyophilized in a lyophilizer.

(Example 2)
Peptide Inhibition of Interleukin 23 Binding to Interleukin 23 Receptor Peptide optimization is performed to be active at low concentrations (eg, IC50 <10 nM) but gastrointestinal (GI) stability We have identified a peptide inhibitor of IL-23 signaling. Certain peptides were tested to identify peptides that inhibit the binding of IL-23 to human IL-23R and inhibit IL-23 / IL-23R functional activity as follows. Peptides tested included peptides containing a variety of different cyclization chemistries, including, for example, cyclic amides (side chain cyclization), such as peptides containing a disulfide link between two Pen residues, and thioether linkage. Peptides containing the above were included. Peptide inhibitors of the present invention include, but are not limited to, peptides having any of the structures shown herein. In addition, the peptide inhibitors of the invention include those having the amino acid sequence or structure of the same peptide described herein and have the same or any N-terminal or C-terminal "capping" group, such as Ac or NH _2. You don't have to have such things.

The assays performed to determine peptide activity are listed below and the results of these assays are presented in Tables E3A-E3H, E4A and E4B, E5A-E5C, E6, E7, and E8. Human ELISA presents the following IL23-IL23R competitive binding assay, rat ELISA presents the following rat IL-23R competitive binding ELISA assay, and pStat3HTRF presents the following DB cell IL-23R pSTAT3 cell assay. The peptides shown in Tables E3B-E3E are cyclized via disulfide bridges formed between two cysteine residues within these peptides. The peptides shown in Table E3F are dimerized via the linker moiety or through the internal cysteine moiety, as shown. The peptides shown in Tables E4A and E4B are cyclized via the two Pen residues present in each of these peptides. The peptides shown in Table E5A are cyclized via thioether bonds between the amino acid residues shown. Table E5B presents an exemplary structure indicating thioether cyclization, which is indicated by the term "cyclo" in the table, with the cyclic region immediately followed by square brackets. The monomeric subunits of the peptide dimer shown in Table E5C are cyclized as indicated by the term "cyclo" and are linked to each other via the indicated linkers. The peptides shown in Table E6 are those cyclized by ring-closing metathesis of the residues shown. Table E7 presents two exemplary structures showing side chain cyclization via cyclic amides, in which the peptides in this table are cyclized as indicated according to the term "cyclo". There is. Table E8 shows peptides cyclized via cysteine and Pen residues.

The peptide inhibitors of the present invention include both cyclized and non-cyclized forms of the peptides shown herein. For certain peptides, the residue Abu is present as indicated, but in other embodiments related to the non-cyclized form, the Abu is referred to as hSer (Cl) or homo Ser residue. Can be done.

IL23-IL23R Competitive binding ELISA
Immunon® 4HBX plates were coated with 50 ng IL23R_huFC per well and incubated overnight at 4 ° C. Wells were washed 4 times with PBST, blocked with PBS containing 3% skim milk for 1 hour at room temperature, and washed again with PBST 4 times. A serial dilution of test peptide and IL-23 diluted in assay buffer (PBS containing 1% defatted milk) at a final concentration of 2 nM was added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected by incubating 50 ng per well with goat anti-p40 polyclonal antibody (R & D Systems # AF309) diluted in assay buffer for 1 hour at room temperature. The wells were washed again with PBST four times. A donkey anti-goat IgG (Jackson ImmunoResearch Laboratories # 705-035-147) conjugated with HRP, a secondary antibody diluted 1: 5000 in assay buffer, was then added and incubated for 30 minutes at room temperature. The plate was finally washed as described above. The signal was visualized using TMB One Component HRP Membrane Substrate, quenched with 2M sulfuric acid and read spectrophotometrically at 450 nm. IC50 values for the various test peptides determined from these data are shown in Tables E3A-E3H, E4A and E4B, E5A-E5C, E6, E7, and E8.

Rat IL-23R Competitive binding ELISA
Assay plates were coated with 300 ng rat IL-23R_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. The test peptide, a serial dilution of IL-23, and a final concentration of 7 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid. IC50 values for the various test peptides determined from these data are shown in Tables E3G, E3H, E4A, E4B, E5B, E5C and E8.

DB Cell IL23R pSTAT3 Cell Assay IL-23 plays a central role in supporting and maintaining Th17 differentiation in vivo. This process is believed to be mediated primarily by Signal Transducer and Activator of Transition 3 (STAT3), and phosphorylation of STAT3 (which results in pSTAT3) results in RORC and pro-inflammatory IL. Upward control of -17 is guided. This cell assay examines the level of pSTAT3 in IL-23R-expressing DB cells when stimulated with IL-23 in the presence of test compounds. DB cells (ATCC # CRL-2289) cultured in RPMI-1640 medium supplemented with 10% FBS and 1% glutamine (ATCC # CRL-2289) were placed in 96-well tissue culture plates at 5 × 10 ^{5 cells per well.} Seeded. A final concentration of 0.5 nM of test peptide and a serial dilution of IL-23 were added to each well and _{incubated in a 5% CO 2} humidified incubator at 37 ° C. for 30 minutes. Changes in phosphoStat3 levels in cell lysates were detected using the Cisbio HTRF pSTAT3 Cellular Assay Kit according to the manufacturer's Two Plate Assay protocol. IC50 values determined from these data are shown in tables E3E, E3G, E3H, E4A, E4B, E5B, E5C, and E8 as absolute values or in ranges. If not indicated, the data has not been determined.

（配列番号２７５）
SAR analysis of the activity of the peptide inhibitors tested showed that CXXXXXXC disulfides were associated with high activity. Although the two Trp and Ph residues are also associated with high activity, these amino acids can be easily exchanged for similar homologs (eg, Trp substitution at 1-Nal and / or Tyr at Ph). (Replacement of) is recognized. In addition, the data suggested that the presence of one or more basic residues at the C-terminus is associated with high activity. Also, His-9 can be replaced with Arg or another homolog to maintain or improve activity. The schematic below provides one exemplary consensus sequence showing certain residues associated with high activity.

(SEQ ID NO: 275)

(Example 3)
Stability of Peptide Inhibitors under Pseudo-Intestinal Juice (SIF), Pseudogastric Juice (SGF) and Redox Conditions To assess the gastric stability of the peptide inhibitors of the invention, pseudo-intestinal juice (SIF) and pseudogastric juice (SGF) ) Was tested. Furthermore, a test was conducted to evaluate the redox stability of the peptide inhibitor of the present invention.

SIF was prepared by adding 6.8 g of potassium dihydrogen phosphate and 10.0 g of pancreatin to 1.0 L of water. After dissolution, the pH was adjusted to 6.8 using NaOH. DMSO stock (2 mM) was first prepared for the test compound. Aliquots of DMSO solution were placed in 6 individual tubes each containing 0.5 mL of SIF preheated to 37 ° C. The final test compound concentration was 20 μM. Vials were maintained in a benchtop Thermomixer® for the duration of the experiment. At each time point (0 minutes, 5 minutes, 10 minutes, 20 minutes, 40 minutes, 60 minutes, or 360 minutes or 24 hours), 1.0 mL of acetonitrile containing 1% formic acid was added to one vial for reaction. It was terminated. Samples were stored at 4 ° C until the end of the experiment. After sampling at the last point, the tubes were mixed and then centrifuged at 3,000 rpm for 10 minutes. The aliquot of the supernatant was removed, diluted 1: 1 in distilled water containing an internal standard and analyzed by LCMS / MS. The remaining percentage at each time point was calculated based on the peak area response ratio to the internal standard of the test compound. Time point 0 was set to 100% and calculated for time point 0 for all later time points. The half-life was calculated by applying it to a first-order exponential decay equation using Graphpad. The stability in the SIF assay is shown in Tables 9 and 10.

SGF was prepared by adding 20 mg of NaCl, 32 mg of butapepsin (MP Biochemicals, Catalog 02102599), and 70 μl of HCl to 10 ml of water (final pH = 2). Aliquots of SGF (0.5 ml each) were preheated to 37 ° C. To initiate the reaction, 1 μl of peptide stock solution (10 mM in DMSO) was added to 0.5 ml of SGF and mixed thoroughly, thus bringing the final peptide concentration to 20 μM. The reaction was incubated at 37 ° C. with gentle shaking. At each time point (0 min, 15 min, 30 min, 60 min), 50 μl of aliquot was removed and added to 200 μl of acetonitrile containing 0.1% formic acid to quench the reaction. Samples were stored at 4 ° C. until the end of the experiment and centrifuged at 10,000 rpm for 5 minutes. The aliquot of the supernatant was removed, diluted 1: 1 in distilled water containing an internal standard and analyzed by LCMS / MS. The remaining percentage at each time point was calculated based on the peak area response ratio to the internal standard of the test compound. Time point 0 was set to 100% and calculated for time point 0 for all later time points. The half-life was calculated by applying it to a first-order exponential decay equation using GraphPad. Stability in the SGF assay is shown in Tables E9 and E10.

For each peptide tested, a DTT stability assay was performed by adding 5 μl of a 10 mM peptide stock solution in DMSO to 100 mM Tris-Cl, pH 7.5, 1 ml (final peptide concentration is 50 μM). At 0 min, 5 μl of freshly thawed 100 mM DTT solution was added to the incubation tube containing the peptide, thus bringing the final DTT concentration to 0.5 mM. The reaction was incubated at room temperature. At different time points up to 120 minutes (20 minutes, 40 minutes, 80 minutes, 120 minutes), 50 μl of aliquot was removed and the reaction was quenched by the addition of 10 μl of 5M acetic acid. Quenched samples (30 μl) were analyzed by reverse phase HPLC and UV absorbance at 220 nm to measure the disappearance of the parent peptide. The half-life was calculated by graphing the remaining oxidized fraction over time and applying it to a first-order exponential decay equation using Excel. The results of these tests are shown in Table E11. All peptides with a half-life greater than 120 minutes were considered stable.

(Example 4)
Peptide Inhibitor Cross-Reactivity The extracellular domain amino acids of human IL-23R are 95%, 77% and 70% identical to cynomolgus monkey IL-23R, rat IL-23R and mouse IL-23R, respectively. Interestingly, the mouse receptor contains an insertion of 21 residues that are not present on the human receptor, mouse receptor, chimpanzee receptor, canine receptor and bovine receptor. These additional amino acids are located in the region where human IL-23R is believed to bind IL-23.

To identify peptide inhibitors that cross-react with species other than human IL-23R, certain peptide inhibitors by ELISA assay are human IL-23R, cynomolgus monkey IL-23R, rat IL-23R and mouse IL-23R. Ability to inhibit. Consistent with the findings regarding sequence differences between human IL-23R and mouse IL-23R, the peptide antagonists tested showed either lack or very weak inhibitory activity in mouse IL-23R ELISA (Table). See E12). In contrast, the antagonists tested so far have shown comparable efficacy against rat receptors and slightly inferior activity against cynomolgus monkey receptors.

The various bioassays performed to determine the efficacy, cross-reactivity and selectivity of IL-23R antagonists are described below.

Assay for specific IL-23R antagonist selectivity Human IL-12Rβ1 ELISA
Assay plates were coated with 100 ng of human IL-12Rβ1_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. A serial dilution of test peptide and IL-23, a final concentration of 2.5 nM, was added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid.

Mouse IL-23R Competitive binding ELISA
Assay plates were coated with 50 ng of mouse IL-23R_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. The test peptide, a serial dilution of IL-23, and a final concentration of 4 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid.

Rat IL-23R Competitive binding ELISA
Assay plates were coated with 300 ng rat IL-23R_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. The test peptide, a serial dilution of IL-23, and a final concentration of 7 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid.

Cynomolgus monkey IL-23R Competitive binding ELISA
Assay plates were coated with 50 ng of cynomolgus monkey IL-23R_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. The test peptide, a serial dilution of IL-23, and a final concentration of 2 nM were added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid.

(Example 5)
NK Cell Assay Natural killer (NK) cells (Miltenyi Biotech, Cat No. 130-092-657) purified by negative selection from human peripheral blood of healthy donors in complete medium (10% FBS, L-glutamine and penicillin- In RPMI1640) containing streptomycin, the cells were cultured in the presence of 25 ng / mL IL-2 (RnD, Cat No. 202-IL-010 / CF). After 7 days, the cells were centrifuged and resuspended at 1 × 10 ⁶ cells per 1mL in complete medium. Predetermined EC50-EC75 recombinant IL-23 and 10 ng / mL IL-18 (RnD, Cat number B003-5) were mixed with peptides of various concentrations and seeded at ^{1 × 10 5 cells per well.} It was added to NK cells. After 20-24 hours, IFNγ in the supernatant was quantified using a Quantikine ELISA (RnD, Cat number DIF50).

(Example 6)
Peptide Inhibitor Bioassay Characteristic The potency, cross-reactivity, and selectivity of a particular peptide inhibitor were determined using the various bioassays developed for this purpose:

Rat Spleen Cell Assay The new assay developed was the rat spleen cell assay. In this assay, the level of IL-17A in activated rat splenocytes after stimulation with IL-23 in the presence of test compound was investigated.

Briefly, splenocytes freshly isolated from rats were seeded in 96-well tissue culture plates in complete medium containing IL-1β. A serial dilution of the test compound was distributed in each well with rat IL-23 at a final concentration of EC50-EC80 values; then the plates were _{incubated in a 5% CO 2} humidified incubator at 37 ° C. for 3 days. Changes in IL-17A levels in the supernatant were detected using ELISA.

Rat colitis model: Drinking water containing 3% DSS for 9 days There is extensive evidence in the literature to support the pathogenic role of IL-23 / IL-23R signaling in animal models of colitis. For IL-23 ligands, this requirement includes the IL-10 ^{− / −} spontaneous colitis model, the Helicobacter hepaticus-driven colitis model, the anti-CD40 congenital colitis model, and the chronic CD45RB ^high CD4 ⁺ T cell transfer model. It has been shown in many models. For IL-23 receptors, requirements for colitis development have been demonstrated in the acute model of colitis induced by DSS or anti-CD40, as well as the chronic CD45RB ^high CD4 ⁺ T cell transfer model. Since certain specific peptide inhibitors of the present invention do not cross-react with mouse-derived IL-23 receptors but recognize rat-derived IL-23 receptors, a rat model of IBD associated with the IL-23 pathway was developed. did.

In this model, colitis was induced in SD rats by free exposure to drinking water containing 3% DSS for 9 days. Disease Activity Index (DAI) score and colon weight: colon length ratio in 3 test groups (rats n = 6 per group): vehicle, 3% DSS, and positive control (sulfasalazine 100 mg / kg, PO) , QD) with 3% DSS. The DAI score consisted of a score from three parameters, including percent weight loss, stool consistency, and a quantitative hemocult score, and a maximum of 3 units could be achieved. DAI scores shown in animals exposed to DSS increased significantly after day 4 (compared to vehicle controls), with peak DAI values reaching approximately 2.5 by the end of the study (day 9). Eye). Treatment of rats exposed to DSS with a positive control (sulfasalazine) reduced the disease score from day 5 (compared to DSS alone). The differences observed in the colon weight: colon length terminal ratio were also significant for DSS-induced disease animals with sulfasalazine treatment and DSS-induced disease animals without sulfasalazine treatment.

ex vivo activity and stability Two peptides (Compound A and Compound B) were selected for use in further biological studies (shown below). One contained a thioether bond and the other contained a Pen-Pen disulfide bond. The activity, selectivity and ex vivo stability profiles of the two compounds are presented herein.

Assays for peptide inhibitor selectivity include measurements of IL-12 production in human IL-12Rb1 ELISA and PHA-activated human PBMC, which are briefly described below.

Human IL-12Rβ1 ELISA
Assay plates were coated with 100 ng of human IL-12Rb1_huFC per well and incubated overnight at 4 ° C. Wells were washed, blocked and washed again. A serial dilution of test peptide and IL-23, a final concentration of 2.5 nM, was added to each well and incubated for 2 hours at room temperature. After washing the wells, bound IL-23 was detected using goat anti-p40 polyclonal antibody and then donkey anti-goat IgG conjugated with HRP. The signal was visualized with TMB One Component HRP Membrane Substrate and quenched with 2M sulfuric acid. Data from these assays are presented herein.

Production of IFNγ by IL-12 in PHA-activated human PBMCs This assay investigated the ability of IL-23R antagonists to neutralize the production of IFNγ protein in IL-12-stimulated human PBMCs. IL-23R peptide inhibitors specific for the IL-23 / IL-23R pathway are not expected to alter the levels of IFNγ produced. The assay tested Compound A and Compound B, and a graph is shown in FIG. 2 showing that they do not alter the level of IFNγ produced at the maximum concentration tested.

In vivo activity Female Prague dolly rats were given 3% (wt / vol) DSS dissolved in drinking water to induce acute colitis. Compound A or B was orally administered at 20 mg / kg or 30 mg / kg three times daily for 9 days starting on the same day as DSS. Compound A was also administered intraperitoneally at 30 mg / kg three times per day. Neutralizing anti-IL-23p19 antibody was used as a comparison and was intraperitoneally administered at 4 mg / kg on the same day as the start of DSS and 5 days after the start of DSS. To quantify clinically active colitis, the Disease Activity Index (DAI) was calculated daily for each animal in three parameters: body weight change (scales 0-3), as shown in Table E15. It was determined as the average of stool consistency (scales 0-3) and fecal occult blood (scales 0-3). At autopsy, the entire colon was removed from the cecum to the rectum. The colon was measured for length, rinsed with PBS to remove feces, weighed, and longitudinally incised to determine macroscopic score. Visible damage to the colon was scored on a scale of 0 to 3 as shown in Table E16.

Table E17 shows that on day 7, treatment with compounds A and B significantly improved the DAI score compared to the vehicle-treated group. FIG. 1 shows the results for the DAI value on day 7. In addition, a significant reduction in the ratio of colon weight to colon length and macroscopic colon score was also observed (Fig. 3). The reduction in inflammation observed with the orally delivered peptide was similar to the effect observed with the neutralizing anti-IL23p19 monoclonal antibody. Statistical analysis of significance was compared to the vehicle-treated group and determined using Student's T-test (GraphPad Prism). ^* P <0.05, ^** p <0.01, ^*** p <0.001, ^*** p <0.0001, and the difference was considered significant.

をさらに特徴付けるためにｉｎ ｖｉｔｒｏアッセイおよびＳＰＲを実施した。
(Example 7)
In vitro Assay and Surface Plasmon Resonance (SPR) Analysis Exemplary Compounds, Compound C:

In vitro assays and SPRs were performed to further characterize.

Performing the assays described in previous examples, compound C is a potent, selective and competitive IL-23R inhibitor of phospho STAT3 (pSTAT3) in human DB cells. It has been demonstrated that it exhibits IL-23-dependent upregulation and strong inhibition of IFNγ production in human peripheral blood natural killer (PB NK) cells. In addition, Compound C was selective, showing only slight inhibition in cell-free ELISA for human IL6R, or IL-12-dependent production of IFNg in PBMC. The data are shown in Table E18A below. Compound C also cross-reacted with crab monkey IL-23R (IC50, 7nM) and rat IL-23R (IC50, 17nM), inhibiting IL-23-dependent IL-17A production in rat splenocytes (IC50, 130nM). (Data not shown).

Exposure to Compound C was also limited to GI after oral administration to rats at a dose of PO, 20 mg / kg, with an AUC value of 355 ug. For the small intestinal mucosa. h / g; 77 ug for colonic mucosa. h / g; and 0.3 ug for plasma. It was h / mL, and the recovery rate in feces was 40%.

Compound C is also stable in a variety of GI solutions and reducing environments, with an SIF half-life> 24 hours; SGF half-life> 24 hours; human intestinal fluid half-life> 24 hours, and a half-life in the DTT assay> 2 hours. there were.

SPR experiments were performed using Biacore 2000 instrument and T100 optical biosensors equipped with Biacore CM4 and Xantec HC1500m sensor chips. Recombinant human IL-23R_huFC (RnD), or recombinant human IL-12Rβ1_huFC (RnD) or a mixture of two receptor subunits was captured on an anti-human IgG surface. Recombinant human IL-23 (Humanzyme) or compound C was used as the analyte. The SPR sensorgrams fit to a one-to-one interaction model, association rate constant _{(k on)} of the street complexes are shown in Table E11, the dissociation rate constant _{(k off)} and a rough estimate a dissociation constant _{(K D)} Got a value. Data show that compound C does not bind to IL-12Rβ1 and binds to IL-23R and mixed surfaces of IL-12Rβ1 and IL-23R with similar potency, 2.42 nM and 2.56 nM, respectively. Is done. The affinity for IL-23R is equivalent to the affinity for IL-23. In contrast, the affinity of IL-23 for mixed surfaces is approximately 14-fold faster than that of compound C.

(Example 8)
Efficacy of IL-23R Antagonists in TNBS-Induced Colitis in Rats To further evaluate the efficacy of IL-23R antagonists in animal models of disease, 45% -50% ethanol in 7-week-old female Sprague dolly rats Acute colitis was induced by intrarectal administration of 60 mg / kg of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in (TNBS / ethanol) on day 0. Compound C (described in Example 7) is orally administered at 20 mg / kg or 6.7 mg / kg three times daily and in drinking water at 0.6 mg / mL or 0.2 mg / mL, respectively. It was provided for 8 days starting approximately 24 hours before TNBS inoculation (1st day). Neutralizing anti-IL-23p19 antibody was used as a comparison and was administered intraperitoneally at 4 mg / kg on day -1 and again on day 3. All animals received the PBS (pH 7.4) vehicle used to formulate Compound C orally. The test design is shown in FIG.

To assess the extent of the inflammatory response, animals were observed daily for clinical signs including percent weight loss and signs of loose stools or diarrhea. Six days after inoculation with TNBS, rats were sacrificed and the total colon length and colon weight from each animal from the cecum to the rectum was recorded. The severity of colitis was assessed by a pathologist who was blinded to the identity of the procedure. In addition to colon wall thickness, macroscopic colonic injury was scored on a scale of 0-4 according to Table E19 below, and histopathological scores were determined based on the parameters below (Tables E20 and E21).

Compared to the sham group, rats attacked with TNBS showed acute weight loss, an increased incidence of loose stools, and an increased ratio of weight to colon length. These data were confirmed by macroscopic examination of the colon, which revealed mild colonic injuries characterized by erythema, edema and small erosions. Treatment with Compound C attenuated these changes compared to the TNBS colitis group. At high doses, Compound C significantly reduced the ratio of weight to colon length, reduced colon wall thickness, and more importantly, improved colon gross pathology scores to normal in 70% of animals. It was valid. Statistical significance was observed at low doses for all of the above indicators, except for colon wall thickness (although the trend was clear). The reduction in inflammation observed with Orally delivered Compound C was similar to the effect observed with the neutralizing anti-IL-23p19 monoclonal antibody (FIG. 6).

H & E-stained distal colon histological examination revealed that the majority of lesions observed in the vehicle group were transmural, with inflammatory cells across the entire thickness of the colon, the presence of necrotic tissue debris on the surface of the lumen , And was shown to be characterized by necrosis with the absence of crypt mucosa. Animals treated with Compound C generally showed localized lesions confined to mucosal and submucosal tissue areas, and colonic tissue showed potential signs of healing at the site of necrosis. Specifically, animals treated with 160 mg / kg / d of Compound C showed significant reductions in inflammation, mucosal necrosis and colon wall thickness, which resulted in a significant overall histological score. It decreased and was comparable to the anti-IL-23p19 antibody control (Fig. 7).

Plasma concentrations of Compound C detected in all animals were determined in a rat splenocyte / IL-17A cell-based assay or in a rat IL-23R ELISA by concentration analysis of samples collected 1 hour after the last PO dose. It has been shown to be less than half the IC75 of the compound given, suggesting that the efficacy observed by oral treatment is most likely due to local activity in the colon. (See FIG. 8). Collectively, these data highlight the protective effect of IL-23R antagonists in the development of TNBS colitis.

From these studies, the peptides of the invention are potent, selective, and orally effective IL-23R peptide antagonists that are promising therapeutic agents for treating IBD and other disorders. It is proved that there is. As shown herein, the present invention is a potent blocker of IL-23 / IL-23R signaling in human cell lines and primary human cells; selective for IL-23R. , And does not inhibit binding to IL-6R or signaling through IL-12R; cross-reactive to rat and citrus monkey homologs but not to mouse homologs, in these species. Vivo testing is possible; resistance to the proteolytic and reducing environment of GI, which results in high drug levels in intestinal tissue and limited drug concentrations in the circulation, systemic delivery It provides a potential safety advantage compared to therapeutic agents that are used; as well as an effective and anti-IL23p19 monoclonal antibody in the attenuation of colitis in a TNBS-induced rat colitis model, most likely due to GI limiting activity. Equivalent, provides a peptide.

ペプチド９９３の構造を以下に示す：

Ａｃ−［（Ｄ）−Ａｒｇ］−シクロ［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２（配列番号９９３）
ペプチド１１８５の構造を以下に示す：

Ａｃ−［Ｐｅｎ］−ＮＴＷＱ−［Ｐｅｎ］−［Ｐｈｅ［４−（２−アミノエトキシ）］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−［Ｌｙｓ（Ａｃ）］−ＮＮ−ＮＨ_２（配列番号１１８５）
ペプチド９８０の構造を以下に示す：

Ａｃ−シクロ−［［Ａｂｕ］−ＱＴＷＱＣ］−［Ｐｈｅ［４−（２−アミノエトキシ）］］−［２−Ｎａｌ］−［４−アミノ−４−カルボキシ−テトラヒドロピラン］−ＥＮＮ−ＮＨ_２（配列番号９８０） (Example 9)
In vitro characterization of exemplary IL-23R antagonists To evaluate the effective properties of the IL-23R peptide antagonists of SEQ ID NOs: 980 (Peptide 980), 993 (Peptide 993), and 1185 (Peptide 1185), Experiments to determine efficacy, selectivity, and stability were performed as described above. Quantitative ELISA for IL-23 / IL-23R competitive binding assay (implemented as described above in Example 2) for binding of human (Hu), cynomolgus monkey (Cyno), and rat IL-23 to IL-23R. _{The IC 50} values of the peptides measured by are shown in Table E22. The efficacy of the peptide was also evaluated by the IL-23R activity assay described above. Due to reduced levels of phosphoSTAT3 (pSTAT3) in human DB cells exposed to IL-23 (Hu DB cells (pSTAT3); performed as described above in Example 2); produced by human NK cells exposed to IL-23. Decreased IFNγ (Hu NK cells; performed as described above in Example 5); and decreased IL-17A produced by activated splenocytes exposed to IL-23 (Rat (spleen); described above in Example 6). IC50 value of the peptide as determined by). Selectivity is the _{IC 50} of the peptide for inhibition of human IL-23 / IL-12R beta 1 (see Example 4) interaction or human IL-6 / IL-6R interaction (see Example 6) Evaluated by measuring. Peptide stability was determined by measuring the half-life of peptides exposed to simulated intestinal fluid (SIF), simulated gastric fluid (SGF), or human intestinal fluid (SIF).

The structure of peptide 993 is shown below:

Ac-[(D) -Arg] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 993)
The structure of peptide 1185 is shown below:

Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1185)
The structure of peptide 980 is shown below:

Ac-cyclo-[[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ ( SEQ ID NO: 980)

From the results summarized in Table E22, the peptides strongly and selectively bind IL-23 / IL-23R as compared to IL-23 / IL-12R beta 1 or IL-6 / IL-6R interactions. Shown to inhibit. This inhibition was confirmed using a cell culture assay that measures IL-23R dependence such as STAT3 phosphorylation, IFNγ production, and IL-17A production. The peptide was also determined to have a high degree of stability when exposed to simulated intestinal fluid, simulated gastric juice, or human intestinal fluid.

Data from human DB cell (pSTAT3) experiments were used for sill analysis (see Figure 17). Peptide 993 at concentrations of 0.3 nM, 1 nM, 3 nM, 10 nM, 30 nM, and 100 nM was tested for sild analysis. The slope of the sill was determined to be 1.068, indicating that peptide 993 behaves as a simple competing antagonist. Schild analysis was also performed on peptides having the structure of SEQ ID NO: 1169, which is highly similar to the structure of peptide 1185. The slope of the sill was determined to be 0.91, indicating that peptides with similar structures, including peptide 1185, may behave as simple competing antagonists. Schild analysis was also performed on the peptide of SEQ ID NO: 1211 having a structure similar to that of peptide 980. The slope of the sill was determined to be 0.76. However, when fixing the inclination to 1, ^{R 2} value was 0.975. These data suggest that peptides with similar structures, including peptide 1185, may behave as simple competing antagonists.

(Example 10)
Pharmacokinetics of an exemplary IL-23R antagonist in vivo The pharmacokinetic properties of an exemplary peptide were measured in vivo. Peptide 993 at 10 mg / kg in Prague dolly rats. O was administered.

A single oral dose of peptide 933 was administered to normal female Prague dolly rats (N = 3 rats per time point) with or without a freely fed drinking water dose (see Figure 11). Exposure to peptide 993 in plasma was determined at 0.25 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 8 hours, and 24 hours after the oral dose. Levels of peptide 993 were also applied to the small intestine, colon, small intestinal mucosa, colonic mucosa, small intestinal mucus, Peyer's patches and mesenteric lymph nodes (MLN) at 1 hour, 3 hours, 6 hours, 8 hours and 24 hours after dose. It was decided by. Urine and feces were collected at 6 and 24 hours to determine peptide 993 excretion. Plasma, fecal and tissue samples were stored at −80 ± 10 ° C. prior to analysis. For plasma, 50 μL of sample was used to extract the compound by protein precipitation using a quench solution with an internal standard (MeOH: ACN w / 0.1% formic acid, 50:50 volume). For feces, samples were homogenized with 0.1% formic acid in water prior to extraction (water: fecal ratio 4: 1). 50 μL of fecal homogenate was used to extract compounds by protein precipitation using a quench solution with an internal standard (MeOH: ACN w / 0.1% formic acid, 50:50 volume). For tissues such as the colon or small intestine, samples were homogenized with 0.1% formic acid in water prior to extraction (water: tissue ratio 3: 1). For tissues such as Peyer's patches and mesenteric lymph nodes, samples were homogenized with 0.1% formic acid in water prior to extraction (water: tissue ratio 20: 1). 50 μL of tissue homogenate was used to extract the compound by protein precipitation using a quench solution with an internal standard (MeOH: ACN w / 0.1% formic acid, 50:50 volume). The precipitated protein was removed by a filter plate and the collected supernatant was dried and reconstituted. The treated samples were analyzed with an AB / MDS Six API 4000 mass spectrometer. Cations were monitored in multiple reaction monitoring (MRM) mode. The quantification was based on the peak area ratio.

No detectable levels of peptide 993 were observed in rat plasma between 0 and 24 hours post-dose (see Figure 11A). In contrast, detectable levels of peptide 993 were present in Peyer's patches and small intestine for at least 6 hours (see Figures 11B and 11C) and in the colon for at least 8 hours (see Figure 11D) after dose administration. Levels above 5% of the total dose of peptide 993 were detected in rat feces 24 hours after administration, further indicating that peptide 993 has a high degree of oral stability. Taken together, these results demonstrate that peptide 993 is an orally stable GI-restricted peptide that exhibits a high GI content and limited systemic distribution after oral administration.

Peptide 1185 in Prague dolly rats at 10 mg / kg. O was administered. A single oral dose of peptide 1185 was administered to normal female Prague dolly rats (N = 3 rats per time point). Exposure of peptide 1185 in plasma was determined after the oral dose and up to 8 hours after the dose. Urine and feces were collected for up to several hours to determine peptide 1185 excretion (Fig. 18).

Peptide 980 at 10 mg / kg in Prague dolly rats. O was administered. A single oral dose of peptide 980 was administered to normal female Prague dolly rats (N = 3 rats per time point). After oral dose, exposure of peptide 980 in plasma was determined in samples obtained up to 8 hours after dose. Urine and feces were collected for up to several hours to determine peptide 980 excretion (Fig. 19).

(Example 11)
Safety Profiles of Exemplary IL-23R Antagonists We have characterized the safety profiles of exemplary peptide inhibitors. Peptide 993 and Peptide 1185 were evaluated in a safety panel investigating the binding of 44 targets to the panel. Targets included G protein-coupled receptors (GPCRs), transporters such as dopamine transporters (DATs), and ion channels. For all targets, these peptides did not exhibit activity defined by a change in target activity of more than 25% (inhibitory or irritating). The targets tested in the safety panel are listed in Table E24. For each target, peptide 993 and peptide 1185 were determined to be inactive at concentrations up to 10 μM. The safety profile of peptide 980 was evaluated by testing the compounds selected from Table E24. For all of the compounds tested, peptide 980 showed only moderate activity in the acetylcholinesterase assay (33%), otherwise the activity defined by a change in target activity by more than 25% I didn't show it at all.

(Example 12)
Efficacy of an exemplary peptide inhibitor in a rat model of acute colitis To evaluate the efficacy of the exemplary peptide inhibitor peptide 1185 in an animal model of disease, day 0 in 7-week-old female Sprague dolly rats. Acute colitis was induced by intrarectal administration of TNBS in 50% ethanol at 64 mg / kg. Peptide 1185 was orally administered at 37 mg / kg (combination of PO and drinking water) per day from day 1 to day 7 with PO BID. A sham group that was not exposed to TNBS and a TNBS-treated group that was treated with a vehicle were used as controls. For comparison, the neutralizing anti-IL-23p19 antibody was intraperitoneally administered at 4 mg / kg on day 1 and again on day 3, and prednisolone was administered at 10 mg per day. O was administered. All animals received the water used to formulate peptide 993 orally as a vehicle.

As mentioned above, animals were observed daily for clinical signs including percent weight loss and signs of loose stools or diarrhea. Six days after inoculation with TNBS, rats were sacrificed and total colon length and colon weight from each animal were recorded. The severity of colitis was assessed by a pathologist. In addition to colon wall thickness, macroscopic colonic injury was scored on a scale of 0-5 according to Table E29, and histopathological scores were determined based on the parameters listed in Table E30.

Treatment with peptide 1185 significantly reduced some of the disease parameters observed in the TNBS rat model of acute colitis. Rats in the sham group continued to gain weight over the course of the study, but rats exposed to TNBS and treated with vehicles lost weight. Oral treatment with prednisolone or systemic treatment with anti-IL-23p19 prevented weight loss in rats exposed to TNBS. Oral treatment with peptide 1185 did not significantly prevent weight loss in TNBS-attacked rats (see Figure 13). After treatment with prednisolone or anti-IL-23p19, a significant reduction in the ratio of colon weight to colon length was also observed compared to treatment with vehicle. Oral administration of peptide 1185 resulted in a similar reduction in the ratio of colon weight to colon length and macroscopic colon score in rats exposed to TNBS. A higher macroscopic colon score indicates a higher degree of colonic pathology. Combine scores for adhesions, stenosis, ulcers, and colon wall thickness, all of which were significantly reduced by treatment with prednisolone, anti-IL-23p19, or peptide 1185 compared to vehicle-treated controls. The macroscopic score of the colon was determined by doing so. These data demonstrate that oral administration of peptide 1185 is as effective as systemic administration of anti-IL-23p19 monoclonal antibody.

Pathological features of colon-derived tissue sections obtained from rats in the sham, vehicle, anti-IL-23p19, and peptide 1185 groups were examined. Mucosal inflammation, transmural inflammation, glandular loss, and erosion were scored according to the criteria listed in Table E29. For all of these features, treatment with anti-IL-23p19 or prednisolone reduced the histopathological score associated with TNBS exposure. Treatment with peptide 1185 did not significantly reduce histopathological scores.

(Example 13)
Efficacy of an exemplary peptide inhibitor in a rat model of acute colitis To evaluate the efficacy of the exemplary IL-23R peptide inhibitor peptide 993 in an animal model of disease, in 7-week-old female Sprague dolly rats. Acute colitis was induced by intrarectal administration of TNBS in 50% ethanol at 64 mg / kg on day 0. Peptide 993 was orally administered twice daily at 10 mg / kg, for a total of 42 mg / kg per day, starting approximately 24 hours before TNBS inoculation (day -1) for 8 days. A sham group that was not exposed to TNBS and a TNBS-treated group that was treated with a vehicle were used as controls. All animals received the water used to formulate peptide 993 orally as a vehicle.

As mentioned above, animals were observed daily for clinical signs including percent weight loss and signs of loose stools or diarrhea. Six days after inoculation with TNBS, rats were sacrificed and total colon length and colon weight from each animal were recorded. The severity of colitis was assessed by a pathologist. In addition to colon wall thickness, macroscopic colonic injury was scored on a scale of 0-5 according to Table E29, and histopathological scores were determined based on the parameters listed in Table E30.

Treatment with peptide 993 significantly reduced all disease parameters observed in the TNBS rat model of acute colitis. Rats in the sham group continued to gain weight over the course of the study, but rats exposed to TNBS and treated with vehicles lost weight. Oral treatment with peptide 993 also prevented weight loss in TNBS-attacked rats (see Figure 12). In addition, a significant reduction in the ratio of colon weight to colon length was also observed after treatment with oral administration of peptide 993. Higher macroscopic colon scores indicated a higher degree of colonic pathology, and treatment with peptide 993 was significantly reduced compared to vehicle-treated controls. Oral administration of peptide 993 is as effective as systemic administration of an anti-IL-23p19 monoclonal antibody that served as a positive control. Histopathological scores were significantly reduced in rat-derived colons treated with peptide 993 compared to the vehicle group.

(Example 14)
Efficacy of an exemplary peptide inhibitor in a rat model of acute colitis To evaluate the efficacy of the exemplary IL-23R peptide inhibitor peptide 980 in an animal model of disease, in 7-week-old female Sprague dolly rats. Acute colitis was induced by intrarectal administration of TNBS in 50% ethanol at 64 mg / kg on day 0. Peptide 980 was orally administered at 37 mg / kg (combination of PO and drinking water) per day from day 1 to day 7 with PO BID. A sham group that was not exposed to TNBS and a TNBS-treated group that was treated with a vehicle were used as controls. All animals received the PBS used to formulate the peptide 980 orally as a vehicle.

As mentioned above, animals were observed daily for clinical signs including percent weight loss and signs of loose stools or diarrhea. Six days after inoculation with TNBS, rats were sacrificed and total colon length and colon weight from each animal were recorded. The severity of colitis was assessed by a pathologist. In addition to colon wall thickness, macroscopic colonic injury was scored on a scale of 0-5 according to Table E29, and histopathological scores were determined based on the parameters listed in Table E30. Treatment with peptide 980 significantly reduced all disease parameters observed in the TNBS rat model of acute colitis.

Oral treatment with peptide 980 prevented weight loss in TNBS-attacked rats (see Figure 14). In addition, a significant reduction in the ratio of colon weight to colon length was also observed after treatment with oral administration of peptide 980. Higher macroscopic colon scores showed a higher degree of colonic pathology, and treatment with peptide 980 significantly reduced compared to vehicle-treated controls (see Figure 14).

Pathological features of colon-derived tissue sections obtained from rats in the sham, vehicle, and peptide 980 treatment groups were examined. Mucosal inflammation, transmural inflammation, glandular loss, and erosion (see Figure 14D) were scored according to the criteria listed in Table E30. The total histopathological score was significantly reduced by treatment with peptide 980 compared to the vehicle.

(Example 15)
Levels of biomarkers after treatment with peptide inhibitors in a rat model of acute colitis The levels of inflammatory markers in the colon were investigated. Distal colon tissue samples designated for protein expression analysis were snap frozen after collection. For protein extraction, samples were thawed, weighed and homogenized in extraction buffer (PBS supplemented with protease inhibitor, pH 7.2, 3 x volume: weight). Debris was removed by centrifuging the homogenate twice at 4 ° C. and 13 kHz for 15 minutes. The supernatant was stored as multiple aliquots at −80 ° C. and then used for protein expression analysis in ELISA. Total protein in each sample was quantified using the BCA assay. Expression of MPO, IL-1β, IL-6, IL-17A and IL-22 proteins in distal colon samples was analyzed using a commercially available rat ELISA kit.

Treatment with peptide 993 reduced the levels of inflammatory markers present in the colon. Disease-defining biomarkers (MPO, IL-6 and IL-1 beta) and IL-23-inducible biomarkers (IL-22, and IL-17A) were treated with peptide 993 to control vehicle treatment. It decreased in comparison (see FIG. 15). These data demonstrate that administration of peptide 993 in an amount capable of reducing pathology in vivo also reduces the levels of biomarkers present in the colon associated with IL-23R activity. To. Treatment with peptide 980 reduces MPO and IL-22 levels compared to vehicle-treated controls (see Figure 16). Treatment with peptide 1185 at the tested dose did not significantly reduce MPO, IL-22, or IL-17A levels.

(Example 16)
Characteristics of Inhibition of Interleukin 23 Binding to Interleukin 23 Receptor by Additional Peptides Peptide optimization is performed to be active at low concentrations (eg, IC50 <10 nM), but in the gastrointestinal (GI). An additional peptide inhibitor of IL-23 signaling has been identified that exhibits the stability of. Specific peptides were tested to identify peptides that inhibit the binding of IL-23 to human IL-23R and inhibit IL-23 / IL-23R functional activity, as described below. The peptides tested included peptides containing a variety of different cyclization chemistries, including, for example, peptides containing a disulfide link between two Pen residues, and peptides containing a thioether link. .. Peptide inhibitors of the present invention include, but are not limited to, peptides having any of the structures shown herein. In addition, the peptide inhibitors of the invention include those having the amino acid sequence or structure of the same peptide described herein and have the same or any N-terminal or C-terminal "capping" group, such as Ac or NH _2. You don't have to have such things.

The assay performed to determine peptide activity was performed as described in Example 2 above. Human ELISA presents the IL23-IL23R competitive binding assay, rat ELISA presents the rat IL-23R competitive binding ELISA assay, and pStat3HTRF presents the DB cell IL-23R pSTAT3 cell assay. The peptides shown in Table E31 are cyclized via disulfide bridges formed between two residues within these peptides. The peptides shown in Table E32 are cyclized via thioether bonds between the amino acid residues shown. Table E32 presents an exemplary structure showing thioether cyclization, which is indicated by the term "cyclo" in the table, with the cyclic region immediately followed by square brackets.

(Example 17)
Stability of Additional Peptide Inhibitors under Pseudo-Intestinal Juice (SIF), Pseudogastric Juice (SGF) and Redox Conditions To assess the gastric stability of the additional peptide inhibitors of the invention, Pseudo-Intestinal Juice (SIF) ) And simulated gastric juice (SGF). In addition, tests were conducted to evaluate the redox stability of the additional peptide inhibitors of the present invention.

(Example 18)
NK Cell Assay Natural killer (NK) cells (Miltenyi Biotech, Cat No. 130-092-657) purified by negative selection from human peripheral blood of healthy donors in complete medium (10% FBS, L-glutamine and penicillin- In RPMI1640) containing streptomycin, the cells were cultured in the presence of 25 ng / mL IL-2 (RnD, Cat No. 202-IL-010 / CF). After 7 days, the cells were centrifuged and resuspended at 1 × 10 ⁶ cells per 1mL in complete medium. Predetermined EC50-EC75 recombinant IL-23 and 10 ng / mL IL-18 (RnD, Cat number B003-5) were mixed with peptides of various concentrations and seeded at ^{1 × 10 5 cells per well.} It was added to NK cells. After 20-24 hours, IFNγ in the supernatant was quantified using a Quantikine ELISA (RnD, Cat number DIF50). The results are shown in Table E34. If multiple results are shown for a single peptide, the results are from separate assays.

All of the above US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications and non-patent publications referenced herein and / or listed in the application datasheet are: All of them are incorporated herein by reference.

From the above, although specific embodiments of the present invention have been described herein for illustration purposes, it will be appreciated that various modifications can be made without departing from the gist and scope of the invention. .. Therefore, the present invention is not limited to the scope of the appended claims.
For example, the present invention provides the following items.
(Item 1)
A peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt or solvate thereof, wherein the peptide inhibitor is of formula (Xa):
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Xa)
Containing the amino acid sequence of
X1 is any amino acid or is absent;
X2 is any amino acid or is absent;
X3 is any amino acid or is absent;
X4 is any amino acid or chemical moiety capable of forming a bond with X9;
X5 is any amino acid;
X6 is any amino acid;
X7 is any amino acid;
X8 is any amino acid;
X9 is any amino acid or chemical moiety capable of forming a bond with X4;
X10 is any amino acid;
X11 is any amino acid;
X12 is any amino acid;
X13 is any amino acid;
X14 is any amino acid;
X15 is an arbitrary amino acid,
X16 is any amino acid or is absent;
X17 is any amino acid or is absent;
X18 is any amino acid or is absent;
X19 is any amino acid or is absent;
X20 is any amino acid or is absent,
The peptide inhibitor is cyclized by a bond between X4 and X9 and
The peptide inhibitor is a peptide inhibitor that inhibits the binding of interleukin 23 (IL-23) to the IL-23 receptor.
(Item 2)
The peptide inhibitor according to item 1, wherein the bond between X4 and X9 is a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.
(Item 3)
The peptide inhibitor according to item 1, wherein X4 is Cys, X9 is Cys, and the bond is a disulfide bond.
(Item 4)
The peptide inhibitor according to item 1, wherein X4 is Pen, X9 is Pen, and the bond is a disulfide bond.
(Item 5)
The peptide inhibitor according to item 1, which comprises the amino acid sequence of any one of SEQ ID NOs: 365-370 and 857-1029.
(Item 6)
The peptide of item 1 comprising the amino acid sequence set forth in any of formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) and (Vh). Inhibitor.
(Item 7)
The following amino acid sequence:
[Palm]-[IsoGlu]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NNNH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-isoGlu-Palm)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (Ac)]-[Lys (Ac)]-NN-NH ₂ ;
[Octanyl]-[IsoGlu]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ ;
[Octanyl]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ ;
[Palm]-[PEG4]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-octanyl)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (PEG4-Palm)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-Palm)]-[2-Nal]-[Aib]-[Lys (Ac)] NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-lauryl)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-Palm)-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-lauryl)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-isoGlu-Palm)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)-(PEG4-isoGLu-lauryl)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-isoGlu-Palm)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (PEG4-isoGlu-lauryl)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (IVA)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (biotin)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -QTWQ- [Pen] -Phe (4-CONH ₂ )-[2-Nal]-[α-MeLys (octanyl)]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen]-[Lys (IVA)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (IVA)]-N −NH ₂ ;
Ac- [Pen]-[Lys (biotin)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (biotin)]-N -NH ₂ ;
Ac- [Pen]-[Lys (octanyl)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (octanyl)]-N −NH ₂ ;
Ac- [Pen]-[Lys (Palm)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-Lys (Palm)]-N- NH ₂ ;
Ac- [Pen]-[Lys (PEG8)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN −NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (PEG8)]-N −NH ₂ ;
Ac- [Pen] -K (Peg11-Palm) TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Peg11-palm) ] -N-NH ₂ ;
Ac- [Pen]-[Cit] -TW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen]-[Lys (Ac)]-TW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ ;
Ac- [Pen] -NT- [Phe (3,4-OCH3) 2] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[ Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen] -NT- [Phe (2,4-CH3) 2] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[ Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen] -NT- [Phe (3-CH3)]-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ ;
Ac- [Pen] -NT- [Phe (4-CH3)]-Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ ;
Ac [(D) Arg]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [ΒAla] -NH ₂ ;
Ac-[(D) Tyr]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N -[ΒAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-QN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-N -NH ₂ ; Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Lys (Ac)]-NH ₂ ; Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- QQ-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-Q- [βAla] -NH2;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Cit] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit] -NNH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit] -Q-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit]-[Lys (Ac) )]-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-[ Cit] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -QN- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -E- [Cit] -Q-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Cit]-N- [Cit] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Cit]-Q- [Cit] -NH ₂ ;
Ac- [Pen]-[Cit] -TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -QNN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -ENQ-NH ₂ ;
Ac- [Pen] -GPWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -PGWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWN- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NSWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -N- [Aib] -WQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN- NH ₂ ;
Ac- [Pen] -NTW- [Aib]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)] N- [Aib] -NH ₂ ; Ac- [Pen] -QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-NN-NH ₂ ; Ac- [Pen]-[Lys (Ac)]-TWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib] -[Lys (Ac)] NNNH ₂ ;
Ac- [Pen] -QVWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NT- [2-Nal] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ ;
Ac- [Pen] -NT- [1-Nal] -Q- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -N- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-LN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-GN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Aib] -N-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH ₂ ;
Ac- [Pen] -NTW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Tic]-[βAla]- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[nLeu]-[βAla]- NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-W- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-S- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-L- [βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[AIB]-[βAla] −NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[N-MeAla]-[ βAla] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2-Nap]-[βAla ] -NH ₂ ;
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [βAla] -NH ₂ ;
Ac-[(D) Arg]-[Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -[Lys (Ac)] NNNH ₂ ;
Biotin- [PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]- NN-NH ₂ ;
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)]-NN-NH ₂ ;
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)]-NN-NH ₂ ;
Ac-E-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ ;
Ac-[(D) Asp]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-R-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ ;
Inoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-F-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ ;
Ac-[(D) Phe]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac- [2-Nal]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-T-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ ;
Ac-L-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ ;
Ac-[(D) Gln]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-[(D) Asn]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ ;
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)-(PEG4-Alexa488)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN -NH ₂ ;
[Alexa488]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]- ENN-NH ₂ ;
[Alexa647]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN -NH ₂ ;
[Alexa-647]-[PEG4]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino- 4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ ;
[Alexa647]-[PEG12]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ ; and
[Alexa488]-[PEG4]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Includes any of carboxy-tetrahydropyran]-[Lys (Ac)] -NN-NH ₂
The peptide inhibitor is cyclized via a disulfide bond between two Pen residues or by a thioether bond between an Abu residue and a Cys residue, and the peptide inhibitor is interleukin 23 ( The peptide inhibitor according to item 1, which inhibits the binding of IL-23) to the IL-23 receptor.
(Item 8)
The peptide inhibitor according to any one of items 1 to 7, further comprising one or more half-life extension portions and / or one or more linker moieties conjugated to the peptide inhibitor.
(Item 9)
The peptide inhibitor according to item 8, wherein the half-life extension moiety is conjugated to the peptide inhibitor via one or more linker moieties.
(Item 10)
Formula I:
R ^1- X-R ² (I)
The peptide inhibitor according to any one of items 1 to 9, which comprises the structure of the above, or a pharmaceutically acceptable salt or solvate compound thereof, wherein R ¹ is a bond, hydrogen, C1 in the formula. ~ C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 alkanoyl, including peptidized version alone or as a spacer of either of those described above; X is an amino acid sequence; R ² is a peptide inhibitor that is OH or NH _2.
(Item 11)
A peptide dimer inhibitor of the interleukin 23 receptor, comprising two peptide monomer subunits linked via one or more linker moieties, each peptide monomer subunit being an item. A peptide dimer inhibitor having the sequence or structure according to any one of 1 to 10.
(Item 12)
The peptide dimer inhibitor of item 11, wherein one or both of the peptide monomer subunits are cyclized by an intramolecular bond between X4 and X9.
(Item 13)
The peptide dimer inhibitor according to item 12, wherein one or both of the intramolecular bonds are disulfide bonds, thioether bonds, lactam bonds, selenoethers, diselenides, or olefin bonds.
(Item 14)
The item according to any one of items 11 to 13, wherein the linker moiety is a diethylene glycol linker, an iminodiacetic acid (IDA) linker, a β-Ala-iminodiacetic acid (β-Ala-IDA) linker, or a PEG linker. Peptide dimer inhibitor.
(Item 15)
Any one of items 11 to 14, wherein the N-terminus of each peptide monomer subunit is connected by the linker moiety, or the C-terminus of each peptide monomer subunit is connected by the linker moiety. The peptide subunit inhibitor according to.
(Item 16)
The peptide inhibitor according to any one of items 1 to 10 or the peptide dimer according to any one of items 11 to 15, further comprising a conjugated chemical substituent.
(Item 17)
The peptide inhibitor or peptide dimer according to item 16, wherein the conjugated chemical substituent is a lipophilic substituent or a polymer moiety.
(Item 18)
The conjugated chemical substituents are Ac, Palm, Gamma Glu-Palm, IsoGlu-Palm, PEG2-Ac, PEG4-IsoGlu-Palm, (PEG) _5- Palm, succinic acid, glutaric acid, pyroglutaric acid. The peptide inhibitor or peptide dimer according to item 16, which is benzoic acid, IVA, octanoic acid, 1,4 diaminobutane, isobutyl, or biotin.
(Item 19)
The peptide inhibitor or peptide dimer according to item 16, wherein the conjugated chemical substituent is polyethylene glycol having a molecular weight of 400 Da to 40,000 Da.
(Item 20)
A sequence encoding one or both of the peptide monomer subunits of the peptide inhibitor according to any one of items 1 to 10 or the peptide dimer inhibitor according to any one of items 11 to 15. Polynucleotide containing.
(Item 21)
A vector comprising the polynucleotide according to item 20.
(Item 22)
A pharmaceutical composition comprising the peptide inhibitor or peptide dimer inhibitor according to any one of items 1 to 19 and a pharmaceutically acceptable carrier, excipient, or diluent.
(Item 23)
22. The pharmaceutical composition according to item 22, further comprising an enteric coating.
(Item 24)
23. The pharmaceutical composition of item 23, wherein the enteric coating protects and releases the pharmaceutical composition within the subject's lower gastrointestinal system.
(Item 25)
Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy with seronegative arthritis, microscopic colitis, collagen-accumulating colitis, favored in subjects Acidic gastroenteritis, colitis associated with radiation or chemotherapy, colitis with congenital immunity impairment as seen in leukocyte adhesion deficiency-1, chronic granulomatosis, glycogenic disease type 1b, Hermannsky Padrack Syndrome, Celiac-East Syndrome, and Wiscott-Aldrich Syndrome, ileal pouchitis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mammary adenitis, celiacitis, cholangitis, periductitis that occur after rectal colonectomy and ileal anastomosis A method for treating inflammation, chronic bronchitis, chronic celiac disease, asthma, psoriasis, psoriatic arthritis, or implant-to-host disease, the effective amount of any of items 1 to 19 for the subject. A method comprising the step of providing the peptide inhibitor or peptide dimer inhibitor according to item 1 or the pharmaceutical composition according to any one of items 22 to 24.
(Item 26)
The pharmaceutical composition is administered to the subject by oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, steam therapy, spray, sublingual, buccal, parenteral, rectal. 25. The method of item 25, provided by intraocular, inhalation, topical, vaginal, or topical route of administration.
(Item 27)
25. The method of item 25, wherein the pharmaceutical composition is orally provided to the subject for treating inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease.
(Item 28)
The pharmaceutical composition is provided to the subject orally, locally, parenterally, intravenously, subcutaneously, intraperitoneally, or intravenously to treat psoriasis. The method according to item 25.
(Item 29)
Item 25 to 28, wherein the peptide inhibitor or the peptide dimer inhibitor inhibits the binding of interleukin 23 (IL-23) to the interleukin 23 receptor (IL-23R). The method described.

Claims (29)

A peptide inhibitor of the interleukin 23 receptor, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is any of the following amino acid sequences or a pharmaceutically acceptable salt thereof:
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 632) );
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [βAla] -NH ₂ (SEQ ID NO: 639);
Ac-[(D) Ph]-[Pen] -NTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Cit]- NN-NH ₂ (SEQ ID NO: 679);
Ac-[(D) Ph]-[Pen] -NTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[achc] -ENN-NH ₂ (SEQ ID NO: 681);
Ac- [Pen] -NTWQ [Pen]-[Phe (4-CONH ₂ )]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 682);
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[achc] -ENN-NH ₂ (SEQ ID NO: 977);
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 980) ;
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[α-methyl-L-leucine] -QN- [βAla] -NH ₂ (SEQ ID NO: 984) );
Ac- (D) Phe- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 992);
Ac-[(D) Arg]-[Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN- NH ₂ (SEQ ID NO: 993);
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[acpc] -ENN-NH ₂ (SEQ ID NO: 1043);
Ac- [Pen] -QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1178);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1183);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1186);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1187);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -N- [βAla] -NH ₂ (SEQ ID NO: 1188);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH ₂ (SEQ ID NO: 1191) );
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH ₂ (SEQ ID NO: 1193) );
Ac- [Pen] -NTW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1194);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla] -NH ₂ (SEQ ID NO: 1197);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla] -NH ₂ (SEQ ID NO: 1198);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-S- [βAla] -NH ₂ (SEQ ID NO: 1200);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2-Nap]-[βAla ] -NH ₂ (SEQ ID NO: 1204);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [βAla] -NH ₂ (SEQ ID NO: 1205);
Biotin- Cyclo [ [PEG4]-[Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1269);
Ac-cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1270);
Ac-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1271);
Ac-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1272);
Ac-E-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1273);
Ac-[(D) Asp]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1274);
Ac-R-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1275);
Ac-[(D) Arg]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1276);
Ac-F-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1277);
Ac-[(D) Ph]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1278);
Ac- [2-Nal]-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1279);
Ac-T-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1280);
Ac-L-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1281);
Ac-[(D) Gln]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1282);
Ac-[(D) Asn]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1283);
Ac-cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)-(PEG4-Alexa Fluor® 488)]-[2-Nal]-[4-amino-4-carboxy -Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1284);
[Alexa Fluor® 488]-[PEG4] -cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1285);
[Alexa Fluor® 647]-[PEG4] -cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy -Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1286);
[Alexa Fluor® 647]-[PEG4]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1287);
[Alexa Fluor® 647]-[PEG12]-[(D) Arg ] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1288); or [Alexa Fluor® 488]-[PEG4]-[(D) Arg] -Cyclo [ [Abu] -QTWQC ] -[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1289)
Including, in the formula,
The peptide inhibitor is cyclized via a disulfide bond between two Pen residues or by a thioether bond between an Abu residue and a Cys residue.
The peptide inhibitor inhibits the binding of interleukin 23 (IL-23) to the IL-23 receptor, and 2-Nal is L-2-naphthylalanine and Abu is 2-aminobutyric acid. , Α-MeLys is α-methyl-L-lysine, α-MeLeu is α-methyl-L-leucine, α-MeSer is α-methyl-L-serine, α-MeVal is α-methyl -L-valine, Achc is 1-aminocyclohexanecarboxylic acid, Acpc is 1-aminocyclopropylcarboxylic acid, Acbc is 1-aminocyclobutanecarboxylic acid, Aib is 2-aminoisobutyric acid, Pen is L-penicillamine, Cit is L-citrulin, 2-Nap is L-2-naptylalanine, and Dap is L-diaminopropionic acid, a peptide inhibitor, or pharmaceutical thereof. Tolerable salt. The following amino acid sequence:
Ac- [Pen] -QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1178);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1183);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1186);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1187);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -N- [βAla] -NH ₂ (SEQ ID NO: 1188);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH ₂ (SEQ ID NO: 1191) );
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH ₂ (SEQ ID NO: 1193) );
Ac- [Pen] -NTW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1194);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla] -NH ₂ (SEQ ID NO: 1197);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla] -NH ₂ (SEQ ID NO: 1198);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-S- [βAla] -NH ₂ (SEQ ID NO: 1200);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2-Nap]-[βAla ] -NH ₂ (SEQ ID NO: 1204);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [βAla] -NH ₂ (SEQ ID NO: 1205);
Biotin- [PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1269);
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]- NN-NH ₂ (SEQ ID NO: 1270);
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1271);
Ac-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]- [Lys (Ac)] -NN-NH ₂ (SEQ ID NO: 1272);
Ac-E-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1273);
Ac-[(D) Asp]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1274);
Ac-R-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1275);
Ac-[(D) Arg]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1276);
Ac-F-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1277);
Ac-[(D) Phe]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1278);
Ac- [2-Nal]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1279);
Ac-T-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1280);
Ac-L-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran ] -ENN-NH ₂ (SEQ ID NO: 1281);
Ac-[(D) Gln]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1282);
Ac-[(D) Asn]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4 -Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1283);
Ac-cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)-(PEG4-Alexa Fluor® 488)]-[2-Nal]-[4-amino-4-carboxy -Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1284);
[Alexa Fluor® 488]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4- Carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1285);
[Alexa Fluor® 647]-[PEG4] -cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-amino-4-carboxy -Tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 1286);
[Alexa Fluor® 647]-[PEG4]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1287);
[Alexa Fluor® 647]-[PEG12]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[ 4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1288); or [Alexa Fluor® 488]-[PEG4]-[(D) Arg] -Cyclo [[Abu] -QTWQC]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1289)
The peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. The peptide inhibitor according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor or a pharmaceutically acceptable salt thereof has the following amino acid sequence:
Ac- [Pen] -QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN -NH ₂ (SEQ ID NO: 1178);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1183);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1186);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]- NH ₂ (SEQ ID NO: 1187);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Lys (Ac)] -N- [βAla] -NH ₂ (SEQ ID NO: 1188);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH ₂ (SEQ ID NO: 1191) );
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH ₂ (SEQ ID NO: 1193) );
Ac- [Pen] -NTW- [Cit]-[Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 1194);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla] -NH ₂ (SEQ ID NO: 1197);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla] -NH ₂ (SEQ ID NO: 1198);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-S- [βAla] -NH ₂ (SEQ ID NO: 1200);
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2-Nap]-[βAla ] -NH ₂ (SEQ ID NO: 1204); or Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac) )]-F- [βAla] -NH ₂ (SEQ ID NO: 1205)
Any of these or pharmaceutically acceptable salts thereof,
The peptide inhibitor is a peptide inhibitor, or a pharmaceutically acceptable salt thereof, which is cyclized via a disulfide bond between Pen residues. Less than:
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[acpc] -ENN-NH ₂ (SEQ ID NO: 1043)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[achc] -ENN-NH ₂ (SEQ ID NO: 977)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 980)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[α-methyl-L-leucine] -QN- [βAla] -NH ₂ (SEQ ID NO: 984) )
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- (D) Phe- [Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN-NH ₂ (SEQ ID NO: 992)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac-[(D) Arg]-[Abu] -QTWQC- [Phe [4- (2-aminoethoxy)]]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran] -ENN- NH ₂ (SEQ ID NO: 993)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a thioether bond between Abu and C. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 632) )
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [βAla] -NH ₂ (SEQ ID NO: 639)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac-[(D) Ph]-[Pen] -NTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[4-Amino-4-carboxy-tetrahydropyran]-[Cit]- NN-NH ₂ (SEQ ID NO: 679)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac-[(D) Ph]-[Pen] -NTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[Achc] -ENN-NH ₂ (SEQ ID NO: 681)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Pen] -NTWQ [Pen]-[Phe (4-CONH ₂ )]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH ₂ (SEQ ID NO: 682)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. Less than:
Ac- [Pen] -NTWQ- [Pen]-[Phe [4- (2-aminoethoxy)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH ₂ (sequence) Number 1183)
Alternatively, the peptide inhibitor according to claim 1, which is a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the peptide inhibitor is via a disulfide bond between Pen residues. A cyclized peptide inhibitor or pharmaceutically acceptable salt thereof. A polynucleotide comprising a sequence encoding the peptide inhibitor according to any one of claims 1 to 15. A vector comprising the polynucleotide according to claim 16. A pharmaceutical composition comprising the peptide inhibitor according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceutical composition according to claim 18, further comprising an enteric coating. 19. The pharmaceutical composition of claim 19, wherein the enteric coating protects and releases the pharmaceutical composition within the subject's lower gastrointestinal system. Inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, celiac disease (non-tropical sprue), enteropathy with seronegative arthritis, microscopic colitis, collagen-accumulating colitis, favored in subjects Acidic gastroenteritis, colitis associated with radiation or chemotherapy, colitis with congenital immunity impairment as seen in leukocyte adhesion deficiency-1, chronic granulomatosis, glycogenic disease type 1b, Hermannsky Padrack Syndrome, Celiac-East Syndrome, and Wiscott-Aldrich Syndrome, ileal pouchitis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes, mammary adenitis, celiacitis, cholangitis, periductitis that occur after rectal colonectomy and talus-anal anastomosis The peptide inhibitor according to any one of claims 1 to 15, or a pharmaceutical agent thereof for treating inflammation, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriatic arthritis, or implant-to-host disease. A composition comprising a qualibly acceptable salt, or the pharmaceutical composition according to any one of claims 18 to 20, wherein the composition or pharmaceutical composition is provided to the subject. , Composition or pharmaceutical composition. The composition or the pharmaceutical composition is administered to the subject by oral, parenteral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, steam therapy, spray, sublingual, buccal, 21. The composition or pharmaceutical composition according to claim 21, characterized in that it is provided by parenteral, rectal, intraocular, inhalation, topical, vaginal, or topical routes of administration. The composition or pharmaceutical composition according to claim 21, for treating inflammatory bowel disease (IBD). The composition or pharmaceutical composition according to claim 21, wherein the composition or the pharmaceutical composition is orally provided to the subject for treating ulcerative colitis. Composition or pharmaceutical composition. The composition or pharmaceutical composition according to claim 21, wherein the composition or the pharmaceutical composition is orally provided to the subject for treating Crohn's disease. Composition or pharmaceutical composition. The composition or pharmaceutical composition of claim 21 for treating psoriasis, wherein the composition or pharmaceutical composition is orally, locally or parenterally to the subject. A composition or pharmaceutical composition, characterized in that it is provided intravenously, subcutaneously, intraperitoneally, or intravenously. The composition or pharmaceutical composition according to claim 21, wherein the composition or pharmaceutical composition for treating ileal pouchitis that occurs after rectal colectomy and ileal-anal anastomosis is oral to the subject. A composition or pharmaceutical composition, characterized in that it is provided locally, parenterally, intravenously, subcutaneously, intraperitoneally, or intravenously. The composition or pharmaceutical composition according to claim 27, wherein the composition or pharmaceutical composition is orally provided to the subject. Any one of claims 21-28, wherein the peptide inhibitor or a pharmaceutically acceptable salt thereof inhibits the binding of interleukin 23 (IL-23) to the interleukin 23 receptor (IL-23R). The composition or pharmaceutical composition according to the section.

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