WO2023099669A1 - Peptide inhibitors of interleukin-23 receptor - Google Patents

Peptide inhibitors of interleukin-23 receptor Download PDF

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Publication number
WO2023099669A1
WO2023099669A1 PCT/EP2022/084077 EP2022084077W WO2023099669A1 WO 2023099669 A1 WO2023099669 A1 WO 2023099669A1 EP 2022084077 W EP2022084077 W EP 2022084077W WO 2023099669 A1 WO2023099669 A1 WO 2023099669A1
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Prior art keywords
seq
aminomethyl
dab
leu
wqc
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PCT/EP2022/084077
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English (en)
French (fr)
Inventor
Henrik Fischer MUNCH
Niels Bjerre HOLM
Rasmus LETH
Bjarne Due Larsen
Jesper Mosolff MATHIESEN
Octav CALDARU
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Zealand Pharma AS
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Zealand Pharma AS
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Priority to JP2024532708A priority Critical patent/JP2024543204A/ja
Priority to CN202280079717.2A priority patent/CN118354781A/zh
Priority to US18/715,410 priority patent/US20250154198A1/en
Priority to CA3240982A priority patent/CA3240982A1/en
Priority to MX2024006556A priority patent/MX2024006556A/es
Priority to IL313185A priority patent/IL313185A/en
Priority to KR1020247021622A priority patent/KR20240111800A/ko
Priority to EP22830694.0A priority patent/EP4440592A1/en
Priority to AU2022402440A priority patent/AU2022402440A1/en
Publication of WO2023099669A1 publication Critical patent/WO2023099669A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptide inhibitors of interleukin-23 receptor (IL-23R), and to their medical use in the treatment and/or prevention of a variety of diseases, conditions or disorders, including inflammatory bowel disease, such as Crohn’s disease, psoriasis, and ulcerative colitis, and other conditions and disorders described herein.
  • IL-23R interleukin-23 receptor
  • Interleukin-23 is a heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit of interleukin- 12 (IL- 12).
  • IL- 12 is a cytokine involved in the development of interferon-gamma (IFN-y)-producing T helper 1 (Th1) cells.
  • IFN-y interferon-gamma
  • Th1 T helper 1
  • IL-6 interleukin-6
  • IL-17 interleukin-17
  • TNF tumor necrosis factor
  • CNS central nervous system
  • IL-23 preferentially acts on memory CD4 + T cells.
  • the receptor that binds IL-23 is the interleukin-23 receptor (IL-23R).
  • IL-23R is a heterodimeric receptor composed of I L-I2RP 1 and IL-23R subunits. Binding of IL-23 to IL-23R activates the JAK-STAT signalling pathway: activating the Janus kinase (JAK) molecules JAK2 and tyrosine kinase 2 (TYK2), as well as the signal transducer and activator of transcription proteins (STATs) STAT1 , STAT3, STAT4, and STAT5. STAT4 activation is substantially weaker and different DNA-binding STAT complexes form in response to IL-23 as compared with IL-12.
  • IL-23R associates constitutively with JAK2 and in a ligand-dependent manner with STAT3.
  • IL-23R is expressed on various adaptive and innate immune cells, including: T-helper 17 (Th17) cells, gamma-delta (y ⁇ 5) T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells. These cells are abundantly found in the intestine. In particular, the gene expression and protein levels of IL-23R at the intestine mucosal surface are found to be elevated in inflammatory bowel disease (IBD) patients. It is thought that IL-23 mediates this effect by promoting the development of a pathogenic CD4 + T cell population that produces IL-6, IL- 17, and TNF.
  • IBD inflammatory bowel disease
  • IL-23 production is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through both T-cell-dependent and independent pathways of intestinal inflammation through effects on Th1 and Th17- associated cytokines.
  • IL-23 is also thought to restrain regulatory T-cell responses in the gut, favoring inflammation.
  • IL-23R polymorphisms have been associated with susceptibility to inflammatory bowel diseases (IBDs), further establishing the critical role of the IL-23 pathway in intestinal homeostasis.
  • IL-23 is thought to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders, such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBDs), e.g., ulcerative colitis and Crohn’s disease.
  • IBDs inflammatory bowel diseases
  • Studies in acute and chronic mouse models of IBD have revealed a primary role of IL-23R and downstream effector cytokines in disease pathogenesis.
  • psoriasis is a chronic skin disease affecting about 2%-3% of the general population. It is known to be mediated by the body’s T cell inflammatory response mechanisms. IL-23 is among one of several interleukins implicated as a key player in psoriasis pathogenesis. It is thought IL-23 maintains chronic autoimmune inflammation via the induction of IL-17, activation of macrophages, and regulation of T memory cells. Additionally, expression of IL-23 and IL-23R has been shown to be increased in tissues of patients with psoriasis, and antibodies that neutralize IL-23 showed IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.
  • Protagonist Therapeutics, Inc. currently have a peptide PTG-200 in Phase II clinical trials for Crohn's disease.
  • Protagonist also have two second generation peptides: PN-235 which has completed Phase I clinical trials and is expected to begin Phase II clinical trials for psoriasis; and PN-232 which is in Phase I clinical trials.
  • Protagonist have filed several patent applications in the area of IL-23R inhibitors: WO 2016/011208, WO 2017/011820, WO 2018/022937, WO 2018/136646, WO 2020/014646, WO 2021/007433,
  • Protagonist also disclose another peptide, Compound C, as an IL-23R inhibitor in WO 2016/011208, WO 2017/011820, and Sayago et al., 2018.
  • WO 2016/011208 discloses oral peptide inhibitors of IL-23R and their use to treat inflammatory bowel diseases.
  • the peptides are up to 20 amino acid residues long, and can optionally contain a single chemical bridge between amino acid residues 4 (X4) and 9 (X9).
  • the chemical bridge may be a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.
  • the chemical bridge is a disulfide or thioether bond.
  • WO 2017/011820 discloses peptide inhibitors of IL-23R nd related compositions and methods of using the peptide inhibitors to treat or prevent a variety of diseases and disorders, including inflammatory bowel diseases.
  • the peptides are up to 20 amino acid residues long, and contain a single chemical bridge between amino acid residues 4 (X4) and 9 (X9).
  • the chemical bridge may be a disulfide bond, a thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond, or an olefin bond.
  • the chemical bridge is a disulfide or thioether bond.
  • WO 2018/022937 discloses peptide inhibitors of IL-23R and their use to treat inflammatory diseases, such as inflammatory bowel disease, Crohn’s disease and psoriasis.
  • the peptides disclosed are up to 39 amino acid residues long, and can optionally have a single disulfide or thioether bond between amino acid residues 5 (X5) and 34 (X34).
  • WO 2018/136646 discloses peptide inhibitors of IL-23R and their use to treat inflammatory diseases including inflammatory bowel disease.
  • the peptides disclosed are up to 24 amino acid residues long, and can optionally have a cross-link between amino acid residues 5 (X4) and 10 (X9).
  • the single cross-link between amino acids residues 5 and 10 may be a intramolecular disulfide or thioether bond.
  • WO 2020/014646 discloses peptide inhibitors of IL-23R and their use to treat or prevent a variety of diseases and disorders including inflammatory bowel diseases.
  • the peptide sequences are 5 to 12 amino acid residues long, and can optionally have an intramolecular bond between amino acid residues 1 (X4) and 6 (X9).
  • the intramolecular bond can be a disulfide bond, thioether bond, a lactam bond, a triazole ring, a selenoether bond, a diselenide bond or a olefin bond.
  • the examples shown have a disulfide or thioether bond.
  • WO 2021/007433 discloses peptide inhibitors of IL-23R and their use to treat or prevent a variety of diseases and disorders including inflammatory bowel diseases.
  • the peptide sequences are 5 to 8 amino acid residues long, and can optionally contain a bond between amino acid residues 1 (X4) and 6 (X9).
  • the bond can be a disulfide or thioether bond.
  • WO 2021/146441 discloses peptide inhibitors of IL-23R and their use to treat or prevent a variety of diseases and disorders including inflammatory bowel diseases.
  • the peptides are up to 14 amino acid residues long, which can optionally have a disulfide or thioether bond between amino acid residues 2 (X4) and 7 (X9).
  • WO 2021/146458 discloses peptide inhibitors of IL-23R and their use to treat or prevent a variety of diseases and disorders including inflammatory bowel disease, Crohn’s disease, ulcerative colitis and psoriasis.
  • the peptides are up to 14 amino acid residues long, which can optionally have a bond between amino acid residues 2 (X4) and 7 (X9).
  • the bond may be a disulfide or thioether bond.
  • Heinis et al., 2020 discloses the development of proteolytically resistant therapeutic peptides for oral administration.
  • the authors generated peptides as inhibitors of coagulation Factor Xia and other peptides as gastrointestinal-protease resistant peptide antagonists of IL-23R.
  • the peptides generated as antagonists of IL-23R comprised of two dithioether bridges (specifically 1,3-dithio-propan-2-one bridges) between two pairs of cysteine residues in the peptide chain.
  • the authors identified peptide I5 as the most promising candidate for further development as an oral treatment of inflammatory disorders such as Crohn’s disease on the basis of IL-23R inhibition.
  • IL-23 pathway which may be used to treat and prevent IL-23-associated diseases, including those associated with autoimmune inflammation in the intestinal tract.
  • compounds and methods for specific targeting of IL-23R from the luminal side of the gut may provide therapeutic benefit to IBD patients suffering from local inflammation of the intestinal tissue.
  • the present invention addresses these needs by providing novel peptide inhibitors that bind IL-23R to inhibit IL-23 mediated signalling.
  • novel peptide inhibitors are also suitable for oral administration due to their stability in the gastrointestinal tract.
  • the present invention relates to compounds which are peptide inhibitors of interleukin-23 receptor (IL-23R).
  • IL-23R interleukin-23 receptor
  • the invention provides a compound having the formula:
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent;
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl optionally substituted with NH2;
  • Z is an amino acid sequence of formula I:
  • X1 is absent or is selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys;
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gin, Vai, lie, N-Me-Ser, and Q(pyrrolidin);
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp;
  • X6 is selected from the group consisting of Gin, Glu, Tyr, Cys, Vai, His, N-Me-GIn, and Q(pyrrolidin);
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2- aminoethoxy)ethoxy)propyl), Phe, Vai, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), ⁇ d ⁇ F(4-F), 4-CI-Phe, alpha-Me-Trp, 3,3-Diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2;
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3, 4-Me-Phe, Bip, and ⁇ d ⁇ 6-F-Trp;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, ⁇ d ⁇ 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His, 3- aminopropanoyl, and GABA, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, 3-(4- Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, ⁇ d ⁇ [3-(3-Pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3- F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3- diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-Pyridyl)-Ala;
  • X14 is absent or is Gly
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a compound having the formula:
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent;
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl;
  • Z is an amino acid sequence of formula la:
  • X1 is absent or is selected from the group consisting of Asp, Glu, Ser, Cys, and Lys;
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gin;
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, and Bip;
  • X6 is selected from the group consisting of Gin, Glu, Tyr and Cys;
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH 2 ;
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala;
  • X14 is absent or is Gly;
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; or a pharmaceutically acceptable salt or solvate thereof.
  • the compound is not:
  • the compound is not:
  • Z is not:
  • I3 (isomer 3) DC(1 a)SC(2a)WQC(2a)WWLC(1 a)R; wherein (1a) is a [2,11] 1,3-dithio-propan-2-one bridge and (2a) is a [4,7] 1 ,3-dithio- propan-2-one bridge.
  • the bridge in X2 and X11 and the bridge in X4 and X7 are not both 1,3-dithio-propan-2-one bridges.
  • the bridge in X2 and X11 and the bridge in X4 and X7 are not both dithioether bridges.
  • X1 is absent or Asp. In some embodiments, X1 is absent.
  • X3 is Ser or lie.
  • X3 is Ser.
  • X5 is Trp or 7-Me-Trp.
  • X5 is Trp.
  • X6 is Gin or Glu.
  • X6 is Gin.
  • X8 is Trp, Tyr, or 4-Me-Phe; wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2.
  • X9 is 2-Nal, Trp, or 3, 4-Me-Phe.
  • X9 is 2-Nal or Trp.
  • X9 is 2-Nal.
  • X10 is Leu, 2-Me-Leu, or 2-Me-Val.
  • X10 is Leu or 2-Me-Leu.
  • X10 is Leu.
  • X12 is Arg, D-Arg, and Dab.
  • X12 is Arg.
  • X13 is absent, 3-(3-Pyridyl)-Ala, or 2-Me-3-(3-Pyridyl)-Ala.
  • X13 is absent.
  • X14 is absent.
  • R 1 is H, C1-2 acyl, or is absent. In some embodiments, R 1 is absent.
  • R 2 is NH2.
  • the length of the bridge between X2 and X11 and/or X4 and X7 is 5 to 10 atoms long.
  • X1 is absent
  • R 1 is absent
  • X2 and X11 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring via the /V- terminus of X2.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11 .
  • the dithioether bridge between X2 and X11 and/or X4 and X7 is of the formula -S-L-Y-L-S-, wherein: each S is a sulfur atom and is part of the amino acid residue at X2 and X11 and/or X4 and X7; each L is independently C1-4 alkylene; and
  • each L is independently C1-2 alkylene.
  • each L is methylene
  • Y is arylene selected from phenylene.
  • Y is phenylene selected from 1 ,2-phenylene, 1 ,3-phenylene, and 1 ,4-phenylene. In some embodiments, Y is 1 ,2-phenylene.
  • the bridge containing a triazole ring between X2 and X11 and/or X4 and X7 contains a 1,2,3-triazole ring.
  • the bridge containing a triazole ring between X2 and X11 and/or X4 and X7 is attached to positions 1 and 4 of the triazole ring.
  • the bridge containing a triazole ring between X2 and X11 and/or X4 and X7 is attached to positions 1 and 5 of the triazole ring.
  • X2 and X11 are amino acid residues who together form a lactam bridge.
  • the location of the amide bond in the lactam bridge is closer to X11 than X2.
  • one of the residues at position X2 and X11 is selected from Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4- aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3- aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-aminomethyl-3- fluoro-phenylacetyl, 4-aminomethyl-2-methyl-phenylacetyl, 4-aminomethyl-3-methyl- phenylacetyl, 4-aminomethyl-2-methoxy-phenylacetyl, 4-aminomethyl-3-methoxy-phenylacety
  • X2 is selected from Lys, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2- aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 4- aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro- phenylacetyl, 4-aminomethyl-3-fluoro-phenylacetyl, 4-aminomethyl-2-methyl-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methyl-phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-2-methoxy-phenylacety
  • X2 is Lys and X11 is Glu; X2 is Orn and X11 is Glu; X2 is bAla and X11 is Glu; X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu; X2 is (3- aminomethyl)benzoyl and X11 is Glu; X2 is (4-aminomethyl)benzoyl and X11 is Glu; X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu; X2 is 2-aminomethyl-phenylacetyl and X11 is Glu; X2 is 3-aminomethyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-phenylacetyl and X11 is Glu; X2 is 6-aminohexanoyl and X11 is Glu; X2 is 6-amino-4-oxa
  • X2 is Lys and X11 is Glu; X2 is (3-aminomethyl)benzoyl and X11 is Glu; or X2 is 4-aminomethyl-phenylacetyl and X11 is Glu.
  • X2 is Lys and X11 is Glu.
  • X2 is selected from Glu and Asp
  • X11 is selected from Lys, Arg, and Dab.
  • X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; or X2 is Asp and X11 is Arg.
  • X2 and X11 are amino acid residues who together form a dithioether bridge.
  • X2 and X11 are each independently selected from Cys and N-Me- Cys. In some embodiments, X2 is Cys and X11 is Cys.
  • X2 and X11 are amino acid residues who together form a bridge containing a triazole ring.
  • one of the residues at position X2 and X11 is selected from Lys(Na), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and the other is selected from Pra, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.
  • X2 is selected from Lys(Ns), azidoacetic acid, and (Ns)-Ala; and X11 is selected from Pra, Glu(propargylamine), and Dab(3-butynoic acid).
  • X2 is Lys(Ns) and X11 is Pra; X2 is azidoacetic acid and X11 is Glu(propargylamine); X2 is azidoacetic acid and X11 is Dab(3-butynoic acid); X2 is (N3)- Ala and X11 is Glu(propargylamine); or X2 is (Ns)-Ala and X11 is Dab(3-butynoic acid).
  • X2 is Lys(Ns) and X11 is Pra.
  • X2 is selected from Pra, and but-3-ynoic acid; and X11 is selected from Dab(azidoacetic acid), and Dab((N3)-Ala).
  • X2 is Pra and X11 is Dab(azidoacetic acid); X2 is Pra and X11 is Dab((N3)-Ala); X2 is but-3-ynoic acid and X11 is Dab(azidoacetic acid); or X2 is but-3- ynoic acid and X11 is Dab((N3)-Ala).
  • X2 is Pra and X11 is Dab(azidoacetic acid); or X2 is Pra and X11 is Dab((N3)-Ala).
  • X2 is but- 3-ynoic acid and X11 is Dab(azidoacetic acid); or X2 is but- 3-ynoic acid and X11 is Dab((N 3 )-Ala).
  • X4 and X7 are amino acid residues who together form a dithioether bridge.
  • X4 and X7 are each independently selected from Cys and N-Me- Cys.
  • X4 is Cys and X7 is Cys; or X4 is N-Me-Cys and X7 is Cys.
  • X4 is Cys and X7 is Cys. In some embodiments, X4 and X7 are amino acid residues who together form a lactam bridge.
  • one of the residues at position X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu.
  • X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu.
  • X4 is Dpr and X7 is Glu; X4 is Dab and X7 is Glu; or X4 is Orn and
  • X7 is Glu
  • X4 is Glu
  • X7 is selected from Lys, Dpr, Dab, and Orn.
  • X4 is Glu and X7 is Lys; X4 is Glu and X7 is Dpr; X4 is Glu and X7 is Orn; or X4 is Glu and X7 is Dab.
  • X4 and X7 are amino acid residues who together form a bridge containing a triazole ring.
  • one of the residues at position X4 and X7 is selected from Lys(Na) and Aha, and the other is Pra.
  • X4 is Lys(Na) and X7 is Pra; or X4 is Aha and X7 is Pra.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2; X10 is D-Leu; and X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2- Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or is absent.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2;
  • X10 is 2-Me-Leu; and
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2- Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent.
  • X8 is His
  • X10 is 2-Me-Leu
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH2-Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2; X10 is D-Leu; and X12 is Arg or is absent.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2; X10 is 2-Me-Leu; and X12 is Arg or is absent.
  • Z is an amino acid sequence selected from the group consisting of:
  • SEQ ID NO: 46 [(3-Aminomethyl)benzoyl](1 c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-
  • Z is an amino acid sequence selected from the group consisting of: S EQ ID NO: 106 [but-3-ynoic acid](1h)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-Nal][2-Me- L eu][Dab(azidoacetic acid)](1h)[ ⁇ d ⁇ R] SEQ ID NO: 107 [but-3-ynoic acid](1h)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-Nal][2-Me- L eu][Dab((N3)-Ala)](1h)[ ⁇ d ⁇ R] SEQ ID NO: 108 [4-Aminomethyl-phenylacetyl](1c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)[ ⁇
  • Z is an amino acid sequence selected from the group consisting of: SEQ ID NO: 1 DC(1a)SC(2a)WQC(2a)WW[2-Me-Leu]C(1a)R SEQ ID NO: 2 LC(1a)SC(2a)WQC(2a)WWLC(1a)R SEQ ID NO: 3 DC(1a)SC(2a)WEC(2a)WWLC(1a)R SEQ ID NO: 4 DE(1c)SC(2a)WQC(2a)WWLK(1c)R SEQ ID NO: 5 DC(1a)SE(2c)WQK(2c)WWLC(1a)R SEQ ID NO: 6 D(1c)*SC(2a)WQC(2a)WWLR(1c)* SEQ ID NO: 9 DE(1c)SC(2a)WQC(2a)WWL[Dab](1c)R SEQ ID NO: 10 E(1c)
  • SEQ ID NO: 46 [(3-Aminomethyl)benzoyl](1 c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-
  • Z is an amino acid sequence selected from the group consisting 10 of: S EQ ID NO: 67 [(3-Aminomethyl)benzoyl](1c)*SE(2c)WQ[Dab](2c)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)R SEQ ID NO: 68 [(3-Aminomethyl)benzoyl](1c)*S[Orn](2c)WQE(2c)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)R SEQ ID NO: 69 [(3-Aminomethyl)benzoyl](1c)*SE(2c)WQ[Orn](2c)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)R SEQ ID NO: 70 [(3-Aminomethyl)benzoyl]
  • Z is an amino acid sequence selected from the group consisting of: S EQ ID NO: 108 [4-Aminomethyl-phenylacetyl](1c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)[ ⁇ d ⁇ R] [4-Aminomethyl-phenylacetyl](1c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2- SEQ ID NO: 109 Nal][2-Me-Leu]E(1c)[ ⁇ d ⁇ 2,4-Diaminobutanoyl([2-(trimethyl-2- aminoethoxy)ethoxy]propyl)] S EQ ID NO: 115 [4-Aminomethyl-phenylacetyl](1c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2- N al
  • specific compounds of the invention include: and pharmaceutically acceptable salts and solvates thereof; wherein:
  • specific compounds of the invention include: and pharmaceutically acceptable salts and solvates thereof; wherein:
  • specific compounds of the invention include: and pharmaceutically acceptable salts and solvates thereof; wherein:
  • the invention further provides a composition comprising a compound as described above.
  • the composition may be a pharmaceutical composition, and may comprise a pharmaceutically acceptable carrier, excipient or vehicle.
  • the invention further provides a method for the synthesis of a compound as described above.
  • the method may comprise the steps of synthesising the peptide by solid-phase or liquid-phase methodology, and optionally isolating and/or purifying the final product, and optionally further comprising the step of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residues at positions X2 and X11, and optionally further comprising the step of forming an amide bond, forming two thioether bonds with a linker, or forming a triazole between the amino acid residues at positions X4 and X7.
  • the invention further provides a compound of the invention, or a pharmaceutical compositions comprising said compound, for use in a method of medical treatment.
  • the invention also provides a compound of the invention, or a pharmaceutical composition comprising said compound, for use in a method of prevention or treatment of Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-l, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis
  • the compound of the invention for use in a method of prevention or treatment of inflammatory bowel (IBD), Crohn’s Disease, ulcerative colitis, and psoriasis.
  • IBD inflammatory bowel
  • Crohn’s Disease Crohn’s Disease
  • ulcerative colitis ulcerative colitis
  • psoriasis a method of prevention or treatment of inflammatory bowel (IBD), Crohn’s Disease, ulcerative colitis, and psoriasis.
  • the invention also provides use of a compound of the invention, or the pharmaceutical composition comprising said compound, in the manufacture of a medicament for the prevention or treatment of Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-l, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, per
  • the use of the compound of the invention, or the pharmaceutical composition comprising said compound in the manufacture of a medicament for the prevention or treatment of inflammatory bowel (IBD), Crohn’s Disease, ulcerative colitis, and psoriasis.
  • IBD inflammatory bowel
  • Crohn’s Disease Crohn’s Disease
  • ulcerative colitis ulcerative colitis
  • psoriasis psoriasis
  • the invention also provides a method of prevention or treatment of Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-l, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, ps
  • the method of prevention or treatment of inflammatory bowel (IBD), Crohn’s Disease, ulcerative colitis, and psoriasis which comprises administering to the subject an effective amount of the compound of the invention, or the pharmaceutical composition comprising said compound.
  • IBD inflammatory bowel
  • Crohn’s Disease Crohn’s Disease
  • ulcerative colitis ulcerative colitis
  • psoriasis which comprises administering to the subject an effective amount of the compound of the invention, or the pharmaceutical composition comprising said compound.
  • patient may be used interchangeably and may refer to either a human or a non-human animal.
  • Subjects are typically mammals, including humans, non-human primates (including great apes, Old World monkeys and New World monkeys), livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats).
  • livestock animals e.g., bovines, porcines
  • companion animals e.g., canines, felines
  • rodents e.g., mice and rats.
  • the term “pharmaceutically acceptable salt” is intended to indicate a salt which is not harmful to a patient or subject to which the salt in question is administered. It may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts.
  • Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type N(R 1 )(R 2 )(R 3 )(R 4 ) + , where R 1 , R 2 , R 3 and R 4 independently will typically designate hydrogen, optionally substituted Ci-6-alkyl or optionally substituted C2-6-alkenyl.
  • Examples of relevant Ci-6-alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl groups.
  • C2-6-alkenyl groups of possible relevance include ethenyl, 1-propenyl and 2-propenyl.
  • Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 1 7t h edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3 rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977).
  • solvate in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in casu, a peptide or pharmaceutically acceptable salt thereof according to the invention) and a solvent.
  • the solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable - typically small- molecular - organic species, such as, but not limited to, acetic acid or lactic acid.
  • a solvate is normally referred to as a hydrate.
  • antagonist as employed in the context of the invention refers to a substance that inhibits the receptor type in question, typically by binding to it (i.e. as a ligand) and blocking it.
  • therapeutically effective amount refers to an amount that is sufficient to cure, ameliorate, alleviate or partially arrest the clinical manifestations of the particular disease, disorder or condition that is the object of the treatment or other therapeutic intervention in question e.g. as measured by established clinical endpoints or other biomarkers (established or experimental).
  • a therapeutically relevant amount may be determined empirically by one skilled in the art based on the indication being treated or prevented and the subject to whom the therapeutically relevant amount is being administered. For example, the skilled worker may measure one or more of the clinically relevant indicators of bioactivity described herein, e.g.
  • MPO myeloperoxidase
  • interleukin-1 p I L-1
  • interleukin-6 IL-6
  • interleukin-22 IL-22
  • interleukin-17A IL-17A
  • interleukin-17F IL-17F
  • lipocalin 2 L1
  • MMP9 matrix metallopeptidase 9
  • S100A8 S100 calcium-binding protein A8
  • microRNA-223-3p microRNA-223-3p
  • Claudin 8 Claudin 8
  • pSTAT3 phosphorylated signal transducer and activator of transcription 3
  • an amount adequate to accomplish any or all of these effects is defined as a therapeutically effective amount.
  • the administered amount and the method of administration can be tailored to achieve optimal efficacy.
  • An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are well known to the skilled person.
  • treatment and grammatical variants thereof (e.g. “treated”, “treating”, “treat”) as employed in the present context refer to an approach for obtaining beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e. not worsening) of state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival relative to expected survival time if not receiving treatment.
  • a subject e.g.
  • a human in need of treatment may thus be a subject already afflicted with the disease or disorder in question.
  • treatment includes inhibition or reduction of an increase in severity of a pathological state or symptoms (e.g. inflammation) relative to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant disease, disorder or condition.
  • prevention and grammatical variants thereof (e.g., “prevented”, “preventing”, “prevent”) as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, “prevention” may refer to prophylactic or preventive measures.
  • beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable.
  • a subject e.g. a human
  • prevention may thus be a subject not yet afflicted with the disease or disorder in question.
  • prevention thus includes inhibiting or slowing the onset of disease relative to the absence of treatment, and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition.
  • amino acid is an organic compound that contains an amino or amine group (- NH2 or -NHR) and a carboxylic acid (-COOH) group.
  • Some amino acids described herein have the amine and carboxylic acid groups attached to the same carbon, called alpha (a) amino acids. Some amino acids described herein have the amine and carboxylic acid groups 1 , 2, 3, 4, 5, or 6 carbon atoms away.
  • beta-alanine (bAla) has the amine and the carboxylic acid groups are 1 carbon away, such that the carbon connected to the amine group and the carbon connected to the carboxylic acid group are adjacent to one another.
  • a side chain amine group may be functionalised into an azide group (-N3), such as Lys(Ns).
  • a side chain amine may be functionalised into an amide with a pendant azide group (-N3), such as in Dab(azidoacetic acid) and Dab((N3)-Ala)).
  • a side chain amine may be functionalised into an amide with a pendant alkyne group, such as in Dab(3-butynoic acid).
  • the side chain carboxylic acid may be functionalised into an amide with a pendant alkyne group, such as in Glu(propargylamine).
  • amino acids are referred to by their full name (e.g. alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g. Ala or A for alanine, Arg or R for arginine, etc.).
  • amino acids i.e. amino acids other than the 20 encoded by the standard mammalian genetic code
  • they are referred to by their full name (e.g. ornithine, etc.)
  • frequently employed three- or four-character codes are employed for residues thereof, including 2-Nal (3-(2-naphthyl)- alanine).
  • N-Me-Trp Na-methyl-L-tryptophan also known as L-abrine
  • (2S)-2-aminohexanedioic acid or L-homoglutamic acid Apm (2S)-2-aminopimelic acid, also known as
  • Orn L-ornithine also known as 2,5-diaminopentanoic acid hLys (2S)-2-amino-7-amino-heptanoic acid, also known as
  • L-homolysine bAla 3-aminopropionic acid also known as beta-alanine or P-alanine beta-homo-Ser L-p-homoserine
  • GABA gamma aminobutyric acid also known as
  • Amino acid residues are amino acid moieties within a peptide chain.
  • Unnatural amino acid residues may be identified as the fragment of the unnatural amino acid defined in a peptide chain (for example, the unnatural amino acid 3-aminomethylbenzoic acid may be identified as the unnatural amino acid residue (3-aminomethyl)benzoyl in a peptide chain).
  • Linear peptides are written from /V-terminus to C-terminus, left to right.
  • Unnatural (or non-naturally occurring) amino acids and unnatural (or non-naturally occurring) amino acid residues are amino acids and amino acid residues that do not naturally occur in peptide chains. Unnatural amino acids may be formed as secondary metabolites in bacteria, fungi, plants, or marine organisms, or they can be synthesised chemically.
  • a thioether is a functional group of the formula R-S-R, wherein R may be any other suitable functional group.
  • a dithioether is a functional group comprising two thioether groups linked together by a linker, such as R-S-L-Y-L-S-R wherein the linker is -L-Y-L-.
  • a triazole (or triazole ring) is a heterocyclic compound with molecular formula C2H3N3, having a five-membered ring of two carbons and three nitrogen atoms.
  • the triazole in the bridge containing a triazole ring is a 1 ,2,3-triazole.
  • head-to-tail cyclisation is cyclisation of the /V-terminal amine (or derivative thereof) and the C-terminal carboxylic acid to form a cyclic peptide. Typically, this cyclisation forms an amide bond.
  • C1-4 alkyl groups that may be present as a group R 1 in the context of compounds of the present invention include, but are not limited to, C1-3 alkyl groups, such as methyl (Me or -CH 3 ), ethyl (-CH2CH3), 1-propyl (-CH2CH2CH3), or 2-propyl (-CH(CH 3 ) 2 ).
  • C1-3 alkyl groups that may be present as a group R 2 and X8 in the context of compounds of the present invention include methyl (Me or -CHs), ethyl (-CH2CH3), 1-propyl (-CH2CH2CH3), and 2-propyl (-CH(CH 3 ) 2 ).
  • the C1-3 alkyl group may be optionally substituted with NH2, such as -CH2CH2NH2.
  • C1-4 alkylene groups C1-4 alkylene groups that may be present as a group L of the dithioether bridge in the context of compounds of the present invention include, but are not limited to, C1-2 alkylene groups, such as methylene (-CH2-) and ethylene (-CH2CH2-).
  • Arylene groups that may be present as a group Y of the dithioether bridge in the context of compounds of the present invention include, but are not limited to, phenylene (such as 1 ,2-phenylene, 1 ,3-phenylene, and 1 ,4-phenylene).
  • bridging moieties noted in the rounded brackets (e.g., (1a), (2a), etc.). These represent chemical bridges between the specific residue pairs. Each rounded bracket will appear twice in the seguence as a pair to indicate a single bridging moiety. Most of the seguences have two bridging moieties, indicated by 4 sets of rounded brackets meaning two bridging moiety pairs.
  • the number in the rounded bracket indicates a specific bridging moiety pair (e.g. “1” indicates a bridge between amino acid residues at positions 2 and 11 , which is also indicated by the sguare bracket notation defining the specific chemical bridge).
  • the letter indicates the type of chemical bridge (e.g. “a” indicates a 1 ,3-dithio-propan-2-one bridge).
  • the specific chemical bridge is defined at the end of the tables, using a sguare bracket (e.g. [2,11], [4,7], etc.) to indicate the amino acid residues using in the bridging moiety as compared to the original starting peptide (the I3 peptide (isomer 3) as described in Example 2), so these may not line-up specifically with the actual amino acid numbering of the SEQ ID NO: (as in some of these seguences for example, the first amino acid residue had been deleted as compared to the original starting peptide).
  • a sguare bracket e.g. [2,11], [4,7], etc.
  • the “*” notation directly after the rounded bracket notation indicates that the terminal -NH2 (if at the start of the seguence i.e. the /V-terminus) or -COOH (if at the end of the seguence i.e. the C-terminus) is used to form the bridge.
  • the bridging moiety is a triazole and the “*” notation is used on the /V-terminus, the terminal -NH2 has been converted to an azide (-N3) of the /V-terminal amino acid residue.
  • Compounds The invention provides compounds which are peptide inhibitors of IL-23R.
  • the invention provides a compound of the formula:
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent;
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl optionally substituted with NH2;
  • Z is an amino acid sequence of formula I:
  • X1 is absent or is selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys;
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gin, Vai, lie, N-Me-Ser, and Q(pyrrolidin);
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp;
  • X6 is selected from the group consisting of Gin, Glu, Tyr, Cys, Vai, His, N-Me-GIn, and Q(pyrrolidin);
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2- aminoethoxy)ethoxy)propyl), Phe, Vai, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), ⁇ d ⁇ F(4-F), 4-CI-Phe, alpha-Me-Trp, 3,3-Diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2;
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3, 4-Me-Phe, Bip, and ⁇ d ⁇ 6-F-Trp;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, ⁇ d ⁇ 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His, 3- aminopropanoyl, and GABA, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, 3-(4- Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, ⁇ d ⁇ [3-(3-Pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3- F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3- diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-Pyridyl)-Ala;
  • X14 is absent or is Gly
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; or a pharmaceutically acceptable salt or solvate thereof; wherein the compound is not:
  • I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2]; wherein (1a) is a [2,11] 1 ,3-dithio-propan-2-one bridge and (2a) is a [4,7] 1 ,3-dithio- propan-2-one bridge.
  • the invention provides a compound of the formula:
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent;
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl; and Z is an amino acid sequence of formula la:
  • X1 is absent or is selected from the group consisting of Asp, Glu, Ser, Cys, and Lys;
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gin;
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, and Bip;
  • X6 is selected from the group consisting of Gin, Glu, Tyr and Cys;
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH 2 ;
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala;
  • X14 is absent or is Gly
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; or a pharmaceutically acceptable salt or solvate thereof; wherein the compound is not:
  • I3 (isomer 3) H-DC(1a)SC(2a)WQC(2a)WWLC(1a)R-[NH2]; wherein (1a) is a [2,11] 1 ,3-dithio-propan-2-one bridge and (2a) is a [4,7] 1 ,3-dithio- propan-2-one bridge.
  • the invention provides a compound of the formula:
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent;
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl optionally substituted with NH2;
  • Z is an amino acid sequence of formula II:
  • X1 is absent or Asp
  • X3 is Ser or lie
  • X5 is T rp or 7-Me-T rp;
  • X6 is Gin or Glu
  • X8 is Trp, Tyr, or 4-Me-Phe; wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2;
  • X9 is 2-Nal, Trp, or 3, 4-Me-Phe;
  • X10 is Leu, 2-Me-Leu, or 2-Me-Val
  • X12 is Arg, D-Arg, and Dab;
  • X13 is absent, 3-(3-Pyridyl)-Ala, or 2-Me-3-(3-Pyridyl)-Ala; X14 is absent;
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring; or a pharmaceutically acceptable salt or solvate thereof; wherein the compound is not:
  • X2 and X11 are amino acid residues who together form a lactam bridge or a dithioether bridge. In some embodiments of formulae I, la, or II, X2 and X11 are amino acid residues who together form a lactam bridge. In some such embodiments, X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4-aminomethyl- phenylacetyl and X11 is Glu; X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.
  • X4 and X7 are amino acid residues who together form a lactam bridge or a dithioether bridge.
  • X4 and X7 are amino acid residues who together form a dithioether bridge.
  • X4 is Cys and X7 is Cys.
  • X4 and X7 are amino acid residues who together form a lactam bridge.
  • X4 is Glu and X7 is Dab.
  • X2 and X11 are amino acid residues who together form a lactam bridge; and X4 and X7 are amino acid residues who together form a lactam bridge or a dithioether bridge.
  • X2 and X11 are amino acid residues who together form a lactam bridge; and X4 and X7 are amino acid residues who together form a dithioether bridge.
  • X2 and X11 are amino acid residues who together form a lactam bridge; and X4 and X7 are amino acid residues who together form a lactam bridge.
  • R 1 is H, C1-4 acyl, benzoyl, C1-4 alkyl, or is absent.
  • R 1 is absent when X 1 is absent.
  • X1 is absent
  • R 1 is absent
  • X2 and X11 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring via the /V- terminus of X2.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11 .
  • R 2 R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl optionally substituted with NH2.
  • R 2 is NHR 3 , OH, or is absent, wherein R 3 is hydrogen or C1-3 alkyl.
  • R 2 is NH2, NH-(CH2)3-NH2 (that is NH-3-aminopropanoyl), OH, or is absent. In some embodiments, R 2 is NHR 3 . In some embodiments, R 2 is NH-(CH2)3-NH2, that is NH-3-aminopropanoyl. In some embodiments, R 2 is NH2. In some embodiments, R 1 is OH. In some embodiments, R 2 is absent. Preferably, R 2 is NH2.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the N-terminus of X2 and the C-terminus of X11.
  • Z Z Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14 (I)
  • X1 is absent or is selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q(pyrrolidin);
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp;
  • X6 is selected from
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and ⁇ d ⁇ 6-F-Trp;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, ⁇ d ⁇ 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His, 3- aminopropanoyl, and GABA, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, 3-(4- Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, ⁇ d ⁇ [3-(3-Pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3- F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3- diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-Pyridyl)-Ala;
  • X14 is absent or is Gly
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.
  • Z is an amino acid sequence of formula la:
  • X1 is absent or is selected from the group consisting of Asp, Glu, Ser, Cys, and Lys;
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gin
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, and Bip;
  • X6 is selected from the group consisting of Gin, Glu, Tyr and Cys;
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH 2 ;
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-CI-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala;
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl;
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent;
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala;
  • X14 is absent or is Gly
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring;
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.
  • Z is an amino acid sequence of formula II:
  • X1 is absent or Asp
  • X3 is Ser or lie
  • X5 is T rp or 7-Me-T rp
  • X6 is Gin or Glu
  • X8 is Trp, Tyr, or 4-Me-Phe; wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2;
  • X9 is 2-Nal, Trp, or 3, 4-Me-Phe;
  • X10 is Leu, 2-Me-Leu, or 2-Me-Val
  • X12 is Arg, D-Arg, and Dab;
  • X13 is absent, 3-(3-Pyridyl)-Ala, or 2-Me-3-(3-Pyridyl)-Ala;
  • X14 is absent; and X2, X4, X7, and X11 are defined as described above for formula I.
  • Z is an amino acid sequence of formula III:
  • Z is an amino acid sequence of formula IV:
  • Z is an amino acid sequence of formula V:
  • X8 is selected from the group consisting of Trp and Tyr, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2;
  • X2 is Lys and X11 is Gin, who together form a lactam bridge;
  • X4 and X7 are both Cys who together form a dithioether bridge.
  • Z is an amino acid sequence selected from the group consisting of:
  • SEQ ID NO: 70 [(3-Aminomethyl)benzoyl](1 c)*SC(2a)[7-Me-Trp]QC(2a)[Y(2- aminoethoxy)][2-Nal][2-Me-Leu]E(1 c)R
  • SEQ ID NO: 71 [(3-Aminomethyl)benzoyl](1c)*SC(2a)[7-Ph-Trp]QC(2a)[Y(2- a minoethoxy)][2-Nal][2-Me-Leu]E(1c)R
  • SEQ ID NO: 72 [(3-Aminomethyl)benzoyl](1c)*SC(2a)[7-(Naphth-2-yl)-Trp]QC(2a)[Y(2- a minoethoxy)][2-Nal][2-Me-Leu]E(1c)R
  • SEQ ID NO: 73 [
  • Z is an amino acid sequence selected from the group consisting of: S EQ ID NO: 106 [but-3-ynoic acid](1h)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-Nal][2-Me- L eu][Dab(azidoacetic acid)](1h)[ ⁇ d ⁇ R] SEQ ID NO: 107 [but-3-ynoic acid](1h)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2-Nal][2-Me- L eu][Dab((N3)-Ala)](1h)[ ⁇ d ⁇ R] SEQ ID NO: 108 [4-Aminomethyl-phenylacetyl](1c)*SC(2a)WQC(2a)[Y(2-aminoethoxy)][2- N al][2-Me-Leu]E(1c)[ ⁇
  • X1 X1 is absent or is selected from the group consisting of Asp, Gly, Leu, Glu, Ser, Cys, and Lys. In some embodiments, X1 is absent or is selected from the group consisting of Asp, Glu, Ser, Cys, and Lys. In some embodiments, X1 may be absent or is selected from the group consisting of Asp, Gly, and Leu. In some embodiments, X1 may be absent or Asp. In some embodiments, X1 is absent, R 1 is absent, and X2 and X11 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring via the N- terminus of X2.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the N-terminus of X2 and the C-terminus of X11.
  • X1 is absent.
  • truncating the compound by removing the N-terminal amino acid residue i.e. X1
  • X3 X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, Gln, Val, Ile, N-Me-Ser, and Q(pyrrolidin).
  • X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Gln, Val, Ile, N-Me-Ser, and Q(pyrrolidin). In some embodiments, X3 is selected from the group consisting of Ser, beta-homo-Ser, Thr, Leu, Cys, and Gin.
  • X3 is Ser or lie.
  • X3 is Ser.
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me-Trp, 7-Me-Trp, 7-Ph-Trp, 7- (Naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp.
  • X5 is selected from the group consisting of Trp, Tyr, Ala, 1-Me- Trp, 7-Me-Trp, 7-Ph-Trp, 7-(Naphth-2-yl)-Trp, 2-Nal, and Bip.
  • X5 is selected from the group consisting of Trp, Ala, 1-Me-Trp, 7- Me-Trp, 7-Ph-Trp, 7-(Naphth-2-yl)-Trp, 2-Nal, Bip, 4-F-Trp, 7-F-Trp, and N-Me-Trp.
  • X5 is Trp or 7-Me-Trp. In some embodiments, X5 is Trp.
  • X6 is selected from the group consisting of Gin, Glu, Tyr, Cys, Vai, His, N-Me-GIn, and Q(pyrrolidin).
  • X6 is selected from the group consisting of Gin, Glu, Vai, His, N- Me-GIn, and Q(pyrrolidin).
  • X6 is selected from the group consisting of Gin, Glu, Tyr and Cys.
  • X6 is Gin or Glu. In some embodiments, X6 is Gin.
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, 2-Nal, Dab, 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2-(trimethyl-2- aminoethoxy)ethoxy)propyl), Phe, Vai, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4-F), ⁇ d ⁇ F(4-F), 4-CI-Phe, alpha-Me-Trp, 3,3-Diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2.
  • X8 is selected from the group consisting of Trp, Tyr, Ala, His, 2- Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2- (trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Vai, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4- F), ⁇ d ⁇ F(4-F), 4-CI-Phe, alpha-Me-Trp, 3,3-Diphenyl-Ala, and Phg, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2.
  • X8 is selected from the group consisting of Trp, Tyr, Ala, His, 2- Nal, Dab, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), F(4-NH2-(2- (trimethyl-2-aminoethoxy)ethoxy)propyl), Phe, Vai, 4-Me-Phe, 2-Me-Phe, Bip, 2-Me-F(4- F), ⁇ d ⁇ F(4-F), 4-CI-Phe, alpha-Me-Trp, 3,3-Diphenyl-Ala, Phg, Y(2-aminoethoxy), and Y(Me).
  • X8 is selected from the group consisting of Trp, Tyr, Asn, Ala, His, and 2-Nal, wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2.
  • X8 is selected from the group consisting of Trp, Tyr, and 4-Me- Phe, wherein the hydroxyl group of Tyr is substituted with C1-3 alkyl optionally substituted with NH2. In some embodiments, X8 is selected from the group consisting of Trp, Tyr, and 4-Me-Phe, wherein the hydroxyl group of Tyr is substituted with -CH2CH2NH2.
  • X8 is Trp or Tyr, wherein the hydroxyl group of Tyr is substituted with C1-3 alkyl optionally substituted with NH2. In some embodiments, X8 is Trp or Tyr, wherein the hydroxyl group of Tyr is substituted with -CH2CH2NH2.
  • X8 is Trp.
  • X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with C1-3 alkyl optionally substituted with NH2. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2 or -CH3. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH2CH2NH2. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH3.
  • X8 is Tyr
  • X8 is Tyr wherein the hydroxyl group of Tyr is substituted with C1-3 alkyl optionally substituted with NH2. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is substituted with C1-3 alkyl substituted with NH2. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is substituted with - CH2CH2NH2, that is Y(2-aminoethoxy). In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is substituted with C1-3 alkyl. In some embodiments, X8 is Tyr wherein the hydroxyl group of Tyr is optionally substituted with -CH3.
  • X8 is Tyr wherein the hydroxyl group of Tyr is substituted with -CH3, that is Y(Me).
  • X8 is selected from Trp, Y(2-aminoethoxy), and 4-Me-Phe. More preferably, X8 is Trp or Y(2-aminoethoxy).
  • X9 X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3- Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and ⁇ d ⁇ 6-F-Trp.
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-Quinolinyl)-Ala, 4-F-Phe, Ala, 6-F-Trp, His, 3-F-Phe, 3,4-Me-Phe, Bip, and ⁇ d ⁇ 6-F-Trp.
  • X9 is selected from the group consisting of 2-Nal, Trp, 1-Me-Trp, 6-Cl-Trp, 3-(3-Quinolinyl)-Ala, Phe, 4-F-Phe, Glu, Cys, and Ala.
  • X9 is selected from the group consisting of 2-Nal, Trp, and 3,4-Me- Phe. In some embodiments, X9 is selected from the group consisting of 2-Nal and Trp. In some embodiments, X9 is Trp. In some embodiments, X9 is 2-Nal. X10 X10 is selected from the group consisting of Leu, D-Leu, 2-Me-Leu, 2-Me-Lys, Trp, Asn, Cys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val.
  • X10 is selected from the group consisting of Leu, D-Leu, 2-Me- Leu, 2-Me-Lys, 4-aminotetrahydro-2H-pyran-4-acetyl, and 2-Me-Val. In some embodiments, X10 is selected from the group consisting of Leu, D-Leu, 2-Me- Leu, 2-Me-Lys, Trp, Asn, Cys, and 4-aminotetrahydro-2H-pyran-4-acetyl. In some embodiments, X10 is selected from the group consisting of Leu, 2-Me-Leu, and 2-Me-Val. In some embodiments, X10 is Leu or 2-Me-Leu. In some embodiments, X10 is
  • X10 is Leu. In some embodiments, X10 is 2-Me-Leu. In some embodiments, X10 is 2-Me-Val.
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4- NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, ⁇ d ⁇ 2,4- diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His, 3- aminopropanoyl, and GABA, or is absent.
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, 4-NH 2 -Phe, Tyr, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, 3-(4-Pyridyl)-Ala, ⁇ d ⁇ 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), D-GIn, D-Glu, D-His,
  • X12 is selected from the group consisting of Arg, D-Arg, 2-Me-Arg, N-Me-Arg, Ser, Phe, 4-NH 2 -Phe, Tyr, Thr, Met, Gly, Glu, Asn, Dab, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala, or is absent.
  • X12 is selected from the group consisting of Arg, D-Arg, Dab, and Gly.
  • X12 is Arg or Ser. In some embodiments, X12 is Arg or D-Arg. In some embodiments, X12 is Arg or Dab. In some embodiments, X12 is D-Arg or Dab.
  • X12 is Arg. In some embodiments, X12 is D-Arg. In some embodiments, X12 is Dab. In some embodiments, X12 is Ser. In some embodiments, X12 is absent.
  • X12 is selected from the group consisting of Arg, D-Arg, and Dab.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11.
  • X13 X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, 3-(4- Pyridyl)-Ala, 3-(3-Quinolinyl)-Ala, ⁇ d ⁇ [3-(3-Pyridyl)-Ala], 3-amino-3-(3'-pyridyl)propionyl, 3- F-Phe, 3,5-F-Phe, 4-aminomethyl-2-pyridineacetyl, 2,3-diaminopropanoyl(3-pyridylacetyl), 2,3-diaminopropanoyl(3-pyridylpropionyl), 2,3-diaminopropanoyl(3-fluorobenzoyl), 2,3- diaminopropanoyl(3-fluorophenylacetyl), and 2-Me-3-(3-Pyridyl)-Ala.
  • X13 is absent or is selected from the group consisting of Asn, Gly, 3-(3-Pyridyl)-Ala, and 3-(4-Pyridyl)-Ala.
  • X13 is absent, 3-(3-Pyridyl)-Ala, or 2-Me-3-(3-Pyridyl)-Ala.
  • X13 is absent. In some embodiments, X13 is Asn. In some embodiments, X13 is Gly. In some embodiments, X13 is 3-(3-Pyridyl)-Ala. In some embodiments, X13 is 2-Me-3-(3-Pyridyl)-Ala.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11 .
  • X13 is 3-(3-Pyridyl)-Ala when X14 is absent, such that X13 is the C-terminal amino acid residue.
  • the potency for hl L23 pSTAT3 is particularly strong, as evidenced by a low IC50 value. See, for example, Compounds 78, 120-124, 147, 148, and 155-158 in Example 3, Table 3-1.
  • X14 is absent or is Gly.
  • X14 is absent. In some embodiments, X14 is Gly.
  • X14 is absent.
  • X13 may be 3-(3-Pyridyl)-Ala.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11 .
  • X2 and X11 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.
  • X2 and X11 are amino acid residues who together form a lactam bridge.
  • a lactam bridge between amino acid residues X2 and X11 is more stable than the corresponding diethioether bridge, 1 ,3-dithio-propan-2-one.
  • X1 is absent
  • R 1 is absent
  • X2 and X11 are amino acid residues that together form a lactam bridge or a bridge containing a triazole ring via the /V- terminus of X2.
  • X1 and X12 to X14 are absent, R 1 and R 2 are absent, and X2 and X11 are amino acid residues that together form a head-to-tail cyclised lactam bridge via the /V-terminus of X2 and the C-terminus of X11 .
  • X2 is Cys and X11 is Cys who together form a dithioether bridge; X2 is Glu and X11 is Lys who together form a lactam bridge; or X2 is Lys and X11 is Glu who together form a lactam bridge.
  • a lactam bridge is formed of one amino acid residue comprising an amine group and another amino acid residue comprising a carboxylic acid group.
  • the amine and/or carboxylic acid group of the amino acid residue is on the side chain of the amino acid residue, such as Dpr, hLys, Lys, Arg, Orn, Dab, Glu and Asp.
  • the amine and/or carboxylic acid group of the amino acid residue may be the N- or C-terminus of the peptide chain, such as the amine or carboxylic acid of the peptide backbone of any amino acid, or such as bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4- aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3- aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4- oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1 -carbonyl, and (4-(2-aminoethyl)- piperazine-1-yl)-acetyl.
  • Suitable amino acid residues for X2 and X11 who together form a lactam bridge may be selected from:
  • Amino acid residues comprising an amine group: Dpr, hLys, Lys, Arg, Orn, bAla, 3- (4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4- (2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoethyl)-piperazine-1-yl)- acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4- methylamino
  • Amino acid residues comprising a carboxylic acid group: Glu, Asp, Aad, and Apm.
  • a dithioether bridge is formed of two amino acid residues comprising sulfur moieties, such as -SH.
  • sulfur moieties such as -SH.
  • the sulfur moiety of the amino acid residue is on the side chain of the amino acid residue, such as Cys.
  • Suitable amino acid residues for X2 and X11 who together form a dithioether bridge may be Cys or N-Me-Cys.
  • a bridge containing a triazole ring is formed of one amino acid residue comprising an azide (-N3) group and another amino acid residue comprising an alkyne group.
  • the azide and/or alkyne groups of the amino acid residue is on the side chain of the amino acid residue.
  • Suitable amino acid residues for X2 and X11 who together form a bridge containing a triazole ring may be selected from:
  • Amino acid residues comprising an azide group: Ala(Ns), Aha, Orn(N3), Lys(Ns), Lys(Ns), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala).
  • Amino acid residues compirising an alkyne group Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.
  • the length of the bridge is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the first residue (X2 for the bridge between X2 and X11), i.e. attached to the alpha carbon of the relevant residue for most amino acids, up to the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the second residue (X11 for the bridge between X2 and X11).
  • the length of the bridge between X2 and X11 is at least 5 atoms long. In some embodiments, the length of the bridge between X2 and X11 is no longer than 10 atoms long. In some embodiments, the length of the bridge between X2 and X11 is 5 to 10 atoms long, such as 5, 6, 7, 8, 9, or 10 atoms long.
  • the inventors have found that replacing a dithioether bridge with a lactam bridge can lead to increased potency (see Example 2) of the IL-23R peptide inhibitor.
  • the compound of the invention may comprises a lactam bridge formed between the amino acid residues at positions X2 and X11.
  • positions X2 and X11 will be discussed by reference to the residues nominally present before lactam formation.
  • One of the residues at positions X2 and X11 is an amino acid residue comprising an amine group and the other is an amino acid residue comprising a carboxylic acid group, wherein a lactam (cyclic amide) is formed between the amine and carboxylic acid groups.
  • the amine and/or carboxylic acid group is present on the side chain of the amino acid residue.
  • the amine may be a primary or secondary amine, but is typically a primary amine.
  • Suitable amino acid residues whose side chains can participate in a lactam bridge include Dpr, Dab, Orn, hLys, Lys, and Arg (having side chains comprising amine groups) and Aad, Apm, Glu, and Asp, (having side chains comprising carboxylic acid groups).
  • Any of the amino acids selected from Aad, Apm, Glu, and Asp may in principle form a lactam bridge with any of the amino acid residues selected from the group consisting of Dpr, Dab, Orn, hLys, Lys, and Arg.
  • the amine and/or carboxylic acid group of the amino acid residue may be the N- or C-terminus of the peptide chain, such as the amine or carboxylic acid of the peptide backbone of any amino acid such as Arg or Asp, or such as bAla, 3-(4- aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2- aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4- aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4- aminomethyl-cyclohexyl-1 -carbonyl, and (4-(2-aminoethyl)-piperazine-1-yl)-acetyl.
  • Suitable amino acid residues that may participate in a lactam bridge via the N- or C- terminus of the peptide chain is Arg, bAla, 3-(4-aminophenyl)propanoyl, (3- aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl- phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6- aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4- (2-aminoethyl)-piperazine-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3- pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl,
  • one of the residues at positions X2 and X11 may be selected from Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4- aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3- aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4- oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoethyl)-piperazine-1- yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4- aminomethyl-2-fluoro-phenyl
  • one of the residues at position X2 and X11 may be selected from Lys, Arg, Orn, bAla, 3-(4-aminophenyl)propanoyl, (3- aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl- phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6- aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1-carbonyl, (4- (2-aminoethyl)-piperazine-1-yl)-acetyl, 4-aminomethyl-2-pyridineacetyl, 4-aminomethyl-3- pyridineacetyl, 4-aminomethyl-2-fluoro-phenylacetyl, 4-
  • X2 may be selected from Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3-(4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4- aminomethyl)benzoyl, 4-(2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3- aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4- oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoethyl)-piperazine-1- yl)-acetyl, 4-
  • X2 may be selected from Lys, Orn, bAla, 3-(4- aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2- aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4- aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4- aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoethyl)-piperazine-1-yl)-acetyl, 4- aminomethyl-2-pyridineacetyl, 4-aminomethyl-3-pyridineacetyl, 4-aminomethyl-2-fluoro- phenylacetyl, 4-aminomethyl-3-methyl-phenylacetyl, 4-aminomethyl-3-me
  • the carboxylic acid component of the lactam bridge derives from the amino acid at position X2, whereas the amine component of the lactam bridge derives from the amino acid at position X11.
  • X2 may be selected from Aad, Apm, Glu, and Asp
  • X11 may be selected from Dpr, Dab, Orn, hLys, Lys, Arg, bAla, 3- (4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4-(2- aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4- aminomethyl-phenylacetyl, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4- aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoe
  • Suitable pairings of residues at positions X2 and X11 to form a lactam bridge include:
  • X2 is Lys and X11 is Glu
  • X2 is Orn and X11 is Glu
  • X2 is bAla and X11 is Glu
  • X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu;
  • X2 is (3-aminomethyl)benzoyl and X11 is Glu;
  • X2 is (4-aminomethyl)benzoyl and X11 is Glu;
  • X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu;
  • X2 is 2-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 3-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 6-aminohexanoyl and X11 is Glu;
  • X2 is 6-amino-4-oxahexanoyl and X11 is Glu;
  • X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu;
  • X2 is (4-(2-aminoethyl)-piperazine-1-yl)-acetyl and X11 is Glu;
  • X2 is (4-(2-aminoethyl)-piperazine-1-yl)-acetyl and X11 is Asp;
  • X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu;
  • X2 Is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu;
  • X2 is Dab and X11 is Glu
  • X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu; or
  • X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.
  • X2 is Glu and X11 is Lys; X2 is Glu and X11 is Dab; or
  • X2 is Asp and X11 is Arg.
  • X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4- aminomethyl-phenylacetyl and X11 is Glu; X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.
  • X2 is (3-aminomethyl)benzoyl and X11 is Glu; X2 is 4- aminomethyl-phenylacetyl and X11 is Glu; or X2 is Lys and X11 is Glu.
  • X2 is (3-aminomethyl)benzoyl and X11 is Glu; or X2 is 4- aminomethyl-phenylacetyl and X11 is Glu.
  • X2 is Glu and X11 is Lys; or X2 is Lys and X11 is Glu.
  • X2 is Lys and X11 is Glu.
  • the contribution of the side chain to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).
  • the contribution of the length of the N- or C-terminus amino acid residue to the length of the lactam bridge is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids), up to and including the atoms which participate in the amide bond of the lactam bridge (i.e. the carbon atom of the carboxylic acid functional group or the nitrogen atom of the amine group).
  • amino acid residues are considered to have the following lengths:
  • the location of the amide bond in the lactam bridge may affect the potency of the compound.
  • the inventors observed that the compound was more active when the amide bond was closer to position 11 (X11) and less active when closer to position 2 (X2) (see Example 2 and Table 2-3b).
  • the amide bond is 4 atoms away from the atom of the peptide backbone of X2 (i.e. to the alpha carbon of Lys) and is 2 atoms away from the atom of the peptide backbone of X11 (i.e. to the alpha carbon of Glu), such that the amide bond is closer to position 11 (X11).
  • the amide bond is 2 atoms away from the atom of the peptide backbone of X11 (i.e. to the alpha carbon of Glu) and is 4 atoms away from the atom of the peptide backbone of X2 (i.e. to the alpha carbon of Lys), such that the amide bond is closer to position 2 (X2).
  • Compound 7, where the amide bond is closer to position 11 (X11), is shown to be more active than Compound 4, where the amide bond is closer to position 2 (X2) in Table 2-3b.
  • Suitable pairings of residues at positions X2 and X11 in which the location of the amide bond in the lactam bridge is closer to position X11 than position X2 once formed include:
  • X2 is Lys and X11 is Glu
  • X2 is Orn and X11 is Glu
  • X2 is 3-(4-aminophenyl)propanoyl and X11 is Glu;
  • X2 is (3-aminomethyl)benzoyl and X11 is Glu;
  • X2 is (4-aminomethyl)benzoyl and X11 is Glu;
  • X2 is 4-(2-aminoethyl)benzoyl and X11 is Glu;
  • X2 is 2-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 3-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-phenylacetyl and X11 is Glu;
  • X2 is 6-aminohexanoyl and X11 is Glu;
  • X2 is 6-amino-4-oxahexanoyl and X11 is Glu;
  • X2 is trans-4-aminomethyl-cyclohexyl-1-carbonyl and X11 is Glu;
  • X2 is (4-(2-aminoethyl)-piperazine-1-yl)-acetyl and X11 is Glu;
  • X2 is (4-(2-aminoethyl)-piperazine-1-yl)-acetyl and X11 is Asp;
  • X2 is 4-aminomethyl-2-pyridineacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-3-pyridineacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-2-fluoro-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-3-fluoro-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-2-methyl-phenylacetyl and X11 is Glu; X2 is 4-aminomethyl-3-methyl-phenylacetyl and X11 is Glu;
  • X2 is 4-aminomethyl-2-methoxy-phenylacetyl and X11 is Glu; or
  • X2 is 4-aminomethyl-3-methoxy-phenylacetyl and X11 is Glu.
  • X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.
  • suitable pairings of residues at positions X2 and X11 in which location of the amide bond in the lactam bridge is closer to position X2 than position X11 include:
  • X2 is bAla and X11 is Glu
  • X2 is Glu and X11 is Lys
  • X2 is Dab (/V-terminus) and X11 is Glu; or
  • X2 is 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl) and X11 is Glu.
  • the side chain of the residue at position X2 is longer than the side chain of the residue at position X11 , such that the location of the amide bond in the lactam bridge is closer to position 11 (X11) than position 2 (X2) once formed.
  • the side chain of the residue at position X2 is longer than the side chain of the residue at position X11.
  • Suitable pairings of residues at positions X2 and X11 in which the side chain at position X2 is longer than the side chain at position X11 include:
  • X2 is Lys and X11 is Glu;
  • X2 is Orn and X11 is Glu.
  • the side chain of the residue at position X2 is shorter than the side chain of the residue at position X11 , such that the location of the amide bond in the lactam bridge is closer to position 2 (X2) than position 11 (X11) once formed.
  • Suitable pairings of residues at positions X2 and X11 in which the side chain at position X2 is shorter than the side chain at position X11 include:
  • X2 is Glu and X11 is Lys.
  • the length of the lactam bridge after formation of the amide bond is 5, 6, 7, 8, 9, or 10 atoms; such as 6, 7, 8, or 9 atoms; such as 7 or 8 atoms.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 5 atoms.
  • a suitable pairing of residues at positions X2 and X11 in which the lactam bridge has a length of 5 atoms include bAla and Glu.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 6 atoms.
  • a suitable pairing of residues at positions X2 and X11 in which the lactam bridge has a length of 6 atoms include Glu and Dab.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 7 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the lactam bridge has a length of 7 atoms include: Orn and Glu; (3-aminomethyl)benzoyl and Glu; and 2-aminomethyl-phenylacetyl and Glu.
  • the length of the lactam bridge after formation of the amide bond is 8 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the lactam bridge has a length of 8 atoms include: Glu and Lys; Aad and Orn; Asp and hLys; (4-aminomethyl)benzoyl and Glu; 3-aminomethyl-phenylacetyl and Glu; 6-aminohexanoyl and Glu; 6-amino-4-oxahexanoyl and Glu; and trans-4- aminomethyl-cyclohexyl-1 -carbonyl and Glu.
  • the length of the lactam bridge after formation of the amide bond is 9 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the lactam bridge has a length of 9 atoms include: 3-(4-aminophenyl)propanoyl and Glu; 4-aminomethyl-phenylacetyl and Glu; (4-(2- aminoethyl)-piperazine-1-yl)-acetyl and Asp; 4-(2-aminoethyl)benzoyl and Glu; 4- aminomethyl-2-pyridineacetyl and Glu; 4-aminomethyl-3-pyridineacetyl and Glu; 4- aminomethyl-2-fluoro-phenylacetyl and Glu; 4-aminomethyl-3-methyl-phenylacetyl and Glu; 4-aminomethyl-3-methoxy-phenylacetyl and Glu; and 4-methylamino
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 10 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the lactam bridge has a length of 10 atoms include: (4-(2-aminoethyl)-piperazine-1-yl)-acetyl and Glu.
  • the compound of the invention may comprise a dithioether bridge formed between the amino acid residues at positions X2 and X11 .
  • positions X2 and X11 will be discussed by reference to the residues nominally present before dithioether formation.
  • the dithioether bridge between X2 and X11 is of the formula -S-L- Y-L-S-, wherein: each S is a sulfur atom and is part of the amino acid residue at X2 and X11 ; each L is independently C1-4 alkylene; and
  • the dithioether bridge of formula -S-L-Y-L-S- is -SCH2(phenylene)CH2S-, such as -SCH2(1 ,2-phenylene)CH2S-, -SCH2(1 ,3- phenylene)CH2S-, and -SCH2(1 ,4-phenylene)CH2S-.
  • the dithioether bridge of formula -S-L-Y-L-S is -SCH2(1 ,2-phenylene)CH2S-. That is, each L is -CH2- and Y is 1 ,2-phenylene.
  • the contribution of the side chain to the length of the dithioether bridge is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atom which participates in the dithioether bond of the bridge (i.e. the sulfur atom).
  • X2 and X11 are each independently selected from Cys and N-Me- Cys.
  • X2 is Cys and X11 is Cys.
  • X2 is Cys and X11 is N-Me-Cys. In some embodiments, X2 is N- Me-Cys and X11 is Cys.
  • X2 is Cys and X11 is Cys.
  • the length of the side chains of X2 and X11 are then added to the contribution of the linker between the sulfur moieties of the amino acid residues at positions X2 and X11 to determine the length of the bridge.
  • the dithioether bridge is of the formula -S-L-Y-L-S-
  • the contribution of the linker is counted as the number of atoms in -L-Y-L-, as the sulfur atoms are already counted in the side chain length.
  • the length of the dithioether bridge after the formation of the dithioether bonds is 5, 6, 7, 8, 9, or 10 atoms, such as 6, 7, 8, or 9 atoms; such as 7, 8, or 9 atoms, such as 7 or 8 atoms.
  • the length of the bridge is 8 atoms long, such as for the bridge -SCH 2 (1 ,2-phenylene)CH 2 S-. In some embodiments, the length of the bridge is 9 atoms long, such as for the bridge -SCH 2 (1 ,3-phenylene)CH 2 S-. In some embodiments, the length of the bridge is 10 atoms long, such as for the bridge -SCH 2 (1 ,4- phenylene)CH 2 S-.
  • the dithioether bridge is 7 or 8 atoms long.
  • Bridge containing a triazole ring is
  • the compound of the invention may comprise a bridge containing a triazole ring formed between the amino acid residues at positions X2 and X11.
  • positions X2 and X11 will be discussed by reference to the residues nominally present before triazole formation.
  • One of the residues at positions X2 and X11 is an amino acid residue comprising an azide (-N3) group and the other is an amino acid residue comprising an alkyne group, wherein a triazole (such as a 1 ,2,3-triazole) is formed between the azide and the alkyne groups.
  • a triazole such as a 1 ,2,3-triazole
  • the reaction for the formation of the triazole ring is a Huisgen azide-alkyne 1 ,3-dipolar cycloaddition. Typically, this reaction forms the 1 ,4-disubstituted 1,2,3-triazole ring (as opposed to the 1,5-disubstitued 1,2,3-triazole ring) as the major isomer.
  • the 1 ,5- dibsubstituted 1 ,2,3-triazole ring may also be isolated, usually as the minor isomer.
  • the azide and/or alkyne group may be present on the side chain of the amino acid residue.
  • Suitable amino acid residues whose side chains can participate in the formation of the triazole ring include Ala(Ns), Aha, Om(Na), and Lys(Ns) (having side chains comprising azide groups) and Pra, Hpg, Bpg, Glu(propargylamine), and Dab(3-butynoic acid) (having side chains comprising alkyne groups).
  • the azide and/or alkyne group of the amino acid residue may be the N- or C- terminus of the peptide chain.
  • the azide group may be derived from the amine group of the peptide backbone of any amino acid, such as azidoacetic acid and (Na)-Ala, and may be the /V-terminus of the peptide chain.
  • the alkyne group may be derived from the amine group of the peptide backbone of any amino acid, such as but-3-ynoic acid, and may be the /V-terminus of the peptide chain.
  • one of the residues at position X2 and X11 may be selected from Ala(Ns), Aha, Om(Na), Lys(Na), azidoacetic acid, (Ns)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other may be selected from Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.
  • one of the residues at position X2 and X11 is selected from Lys(Ns), azidoacetic acid, (Ns)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala), and the other is selected from Pra, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.
  • one of the residues at position X2 and X11 may be Lys(Ns), and the other may be Pra.
  • one of the residues at position X2 and X11 may be Dab(azidoacetic acid) or Dab((N3)-Ala), and the other may be but-3-ynoic acid.
  • the azide component of the bridge containing a triazole ring derives from the amino acid at position X2, whereas the alkyne component of the bridge containing a triazole ring derives from the amino acid at position X11.
  • X2 may be selected from Ala(Ns), Aha, Orn(N3), Lys(N3), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala)
  • X11 may be selected from Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but-3-ynoic acid.
  • X2 is selected from Lys(Ns), azidoacetic acid, and (Ns)-Ala; and X11 is selected from Pra, Glu(propargylamine), and Dab(3-butynoic acid). In some embodiments, X2 is Lys(Ns) and X11 is Pra.
  • the alkyne component of the bridge containing a triazole ring derived from the amino acid at position X2 whereas the azide component of the bridge containing a triazole ring derives from the amino acid at position X11 .
  • X2 may be selected from Pra, Hpg, Bpg, Glu(propargylamine), Dab(3-butynoic acid), and but- 3-ynoic acid
  • X11 may be selected from Ala(Ns), Aha, Orn(N3), Lys(Ns), azidoacetic acid, (Ns)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala).
  • X2 is selected from Pra, and but-3-ynoic acid; and X11 is selected from Dab(azidoacetic acid), and Dab((N3)-Ala). In some embodiments, X2 is but-3-ynoic acid; and X11 is selected from Dab(azidoacetic acid), and Dab((N3)-Ala).
  • Suitable pairings of residues at positions X2 and X11 to form a bridge containing a triazole ring include:
  • X2 is Lys(Ns) and X11 is Pra;
  • X2 is azidoacetic acid and X11 is Glu(propargylamine);
  • X2 is azidoacetic acid and X11 is Dab(3-butynoic acid);
  • X2 is (Ns)-Ala and X11 is Glu(propargylamine); or X2 is (N3)-Ala and X11 is Dab(3-butynoic acid).
  • X2 is the alkyne component and X11 is the azide component: X2 is Pra and X11 is Dab(azidoacetic acid); X2 is Pra and X11 is Dab((N3)-Ala); X2 is but-3-ynoic acid and X11 is Dab(azidoacetic acid); or X2 is but-3-ynoic acid and X11 is Dab((N3)-Ala).
  • the contribution of the side chain to the length of the bridge containing a triazole ring is counted as the number of atoms in a linear chain from the first atom of the side chain (which is bonded to an atom of the peptide backbone, i.e. to the alpha carbon of the relevant residue for most amino acids) up to and including the atoms which participate in the formation of the triazole ring (i.e. the first nitrogen atom of the azide group attached to the side chain (i.e.
  • azide- and alkyne-containing side chains are considered to have the following side chain lengths: Azide-containing side chains: Ala(N 3 ) 2 atoms Aha 3 atoms Orn(N 3 ) 4 atoms Lys(N 3 ) 5 atoms Dab(azidoacetic acid) 6 atoms Dab((N 3 )-Ala) 6 atoms Alkyne-containing side chains (for 1,4-disubstituted 1,2,3-triazoles): Pra 3 atoms
  • Alkyne-containing side chains (for 1,5-disubstituted 1,2,3-triazoles):
  • the contribution of the length of the N- or C-terminus amino acid residue to the length of the bridge containing a triazole ring is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids), up to and including the atoms which participate in the formation of the triazole ring (i.e. the first nitrogen atom of the azide group attached to the side chain (i.e.
  • amino acid residues are considered to have the following lengths:
  • N-terminus azidoacetic acid 1 atom
  • the location of the triazole in the bridge may affect the potency of the compound.
  • Suitable pairings of residues at positions X2 and X11 in which the location of the triazole in the bridge containing a triazole ring is closer to position X11 than position X2 once formed i.e. the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids) up to the triazole ring
  • X2 is Lys(N 3 )
  • X11 is Pra.
  • suitable pairings of residues at positions X2 and X11 in which location of the triazole in the bridge containing a triazole ring is closer to position X2 than position X11 once formed i.e. the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids) up to the triazole ring
  • residues at positions X2 and X11 in which location of the triazole in the bridge containing a triazole ring is closer to position X2 than position X11 once formed i.e. the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid residue (i.e. the first atom attached to the alpha carbon of the relevant residue for most amino acids) up to the triazole ring
  • X2 is Pra and X11 is Dab(azidoacetic acid);
  • X2 is Pra and X11 is Dab((N 3 )-Ala);
  • X2 is azidoacetic acid and X11 is Glu(propargylamine);
  • X2 is azidoacetic acid and X11 is Dab(3-butynoic acid);
  • X2 is (N 3 )-Ala and X11 is Glu(propargylamine);
  • X2 is (N 3 )-Ala and X11 is Dab(3-butynoic acid);
  • X2 is but-3-ynoic acid and X11 is Dab(azidoacetic acid); or
  • X2 is but-3-ynoic acid and X11 is Dab((N 3 )-Ala).
  • the side chain of the residue at position X2 is longer than the side chain of the residue at position X11, such that the location of the triazole in the bridge containing a triazole ring is closer to position 11 (X11) than position 2 (X2) once formed.
  • the side chain of the residue at position X2 is longer than the side chain of the residue at position X11.
  • Suitable pairings of residues at positions X2 and X11 in which the side chain at position X2 is longer than the side chain at position X11 include X2 is Lys(N3) and X11 is Pra.
  • the side chain of the residue at position X2 is shorter than the side chain of the residue at position X11 , such that the location of the triazole in the bridge containing a triazole ring is closer to position 2 (X2) than position (X11) once formed.
  • Suitable pairings of residues at positions X2 and X11 in which the side chain at position X2 is shorter than the side chain at position X11 include:
  • X2 is Pra and X11 is Dab(azidoacetic acid);
  • X2 is Pra and X11 is Dab((N 3 )-Ala).
  • the length of the bridge containing a triazole ring after the formation of the trazole is 5, 6, 7, 8, 9, or 10 atoms, such as 6, 7, 8, or 9 atoms; such as 7, 8, or 9 atoms, such as 8 or 9 atoms.
  • the length of the bridge containing a triazole ring provided by the two side chains after formation of the triazole is 8 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the bridge containing a triazole ring has a length of 8 atoms include: Lys(N 3 ) and Pra; azidoacetic acid and Glu(propargylamine); azidoacetic acid and Dab(3-butynoic acid); (N 3 )-Ala and Glu(propargylamine); (N 3 )-Ala and Dab(3-butynoic acid); but-3-ynoic acid and Dab(azidoacetic acid); and but-3-ynoic acid and Dab((N 3 )-Ala).
  • the length of the bridge containing a triazole ring provided by the two side chains after formation of the triazole is 9 atoms.
  • Suitable pairings of residues at positions X2 and X11 in which the bridge containing a triazole ring has a length of 9 atoms include: Pra and Dab(azidoacetic acid); and Pra and Dab((N 3 )-Ala).
  • X4 and X7 are amino acid residues who together form a lactam bridge, a dithioether bridge, or a bridge containing a triazole ring.
  • X4 and X7 are amino acid residues who together form a lactam bridge.
  • a lactam bridge is more stable than the corresponding dithioether bridge, 1 ,3-dithio-propan- 2-one.
  • dithioether bridge the lactam bridge and the bridge containing a triazole ring is the same as defined for X2 and X11 above.
  • Suitable amino acid residues for X4 and X7 who together form a dithioether bridge may be Cys or N-Me-Cys.
  • Suitable amino acid residues for X4 and X7 who together form a lactam bridge may be selected from:
  • Amino acid residues comprising an amine group: Dpr, hLys, Lys, Arg, Orn, bAla, 3- (4-aminophenyl)propanoyl, (3-aminomethyl)benzoyl, (4-aminomethyl)benzoyl, 4- (2-aminoethyl)benzoyl, 2-aminomethyl-phenylacetyl, 3-aminomethyl-phenylacetyl, 4-aminomethyl-phenylacetyl, Dab, 6-aminohexanoyl, 6-amino-4-oxahexanoyl, trans-4-aminomethyl-cyclohexyl-1 -carbonyl, (4-(2-aminoethyl)-piperazine-1-yl)- acetyl, 2,4-diaminobutanoyl([2-(trimethyl-2-aminoethoxy)ethoxy]propyl), and 4- methylamino
  • Amino acid residues comprising a carboxylic acid group: Glu, Asp, Aad, and Apm.
  • Suitable amino acid residues for X4 and X7 who together form a bridge containing a triazole ring may be selected from:
  • Amino acid residues comprising an azide group: Ala(Ns), Aha, Orn(N3), Lys(Ns), azidoacetic acid, (N3)-Ala, Dab(azidoacetic acid), and Dab((N3)-Ala).
  • the length of the bridge is counted as the number of atoms in a linear chain from the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the first residue (X4 for the bridge between X4 and X7), i.e. attached to the alpha carbon of the relevant residue for most amino acids, up to the first atom attached to the atom (carbon) adjacent to the carboxylic acid moiety of the amino acid of the second residue (X7 for the bridge between X4 and X7).
  • the length of the bridge between X4 and X7 is at least 5 atoms long. In some embodiments, the length of the bridge between X4 and X7 is no longer than 10 atoms long. In some embodiments, the length of the bridge between X4 and X7 is 5 to 10 atoms long, such as 5, 6, 7, 8, 9, or 10 atoms long.
  • the compound of the invention may comprise a dithioether bridge formed between the amino acid residues at positions X4 and X7.
  • the dithioether bridge definitions, such as suitable amino acid residues, as described above for X2 and X11 are applicable here, replacing X2 and X11 for X4 and X7.
  • positions X4 and X7 will be discussed by reference to the residues nominally present before dithioether formation.
  • the dithioether bridge between X4 and X7 is of the formula -S-L-Y- L-S-, wherein: each S is a sulfur atom and is part of the amino acid residue at X4 and X7; each L is independently C1-4 alkylene; and
  • the dithioether bridge of formula -S-L-Y-L-S- is -SCH2(phenylene)CH2S-, such as -SCH2(1 ,2-phenylene)CH2S-, -SCH2(1 ,3- phenylene)CH2S-, and -SCH2(1 ,4-phenylene)CH2S-.
  • the dithioether bridge of formula -S-L-Y-L-S- is -SCH2(1 ,2-phenylene)CH2S-. That is, each L is -CH2- and Y is 1 ,2-phenylene.
  • X4 and X7 are each independently selected from Cys and N-Me- Cys.
  • X4 is Cys and X7 is Cys.
  • X4 is Cys and X7 is N-Me-Cys. In some embodiments, X4 is N- Me-Cys and X7 is Cys.
  • X4 is Cys and X7 is Cys.
  • X4 is Cys and X7 is Cys who together form a dithioether bridge.
  • the definitions for the length of the dithioether bridge as described above for X2 and X11 are applicable here, replacing X2 and X11 for X4 and X7.
  • the dithioether bridge is 7 or 8 atoms long. Lactam bridge
  • the compound of the invention may comprise a lactam bridge formed between the amino acid residues at positions X4 and X7.
  • lactam bridge definitions such as suitable amino acid residues, as described above for X2 and X11 are applicable here, replacing X2 and X11 for X4 and X7.
  • positions X4 and X7 will be discussed by reference to the residues nominally present before lactam formation.
  • one of the residues at position X4 and X7 is Lys, Dpr, Dab, or Orn, and the other is Glu.
  • the amine component of the lactam bridge derives from the amino acid at position X4, whereas the carboxylic acid component of the lactam bridge derives from the amino acid at position X7.
  • X4 is selected from Lys, Dpr, Dab, and Orn, and X7 is Glu.
  • the carboxylic acid component of the lactam bridge derives from the amino acid at position X4, whereas the amine component of the lactam bridge derives from the amino acid at position X7.
  • X4 may be Glu
  • X7 is selected from Lys, Dpr, Dab, and Orn.
  • Suitable pairings of residues at positions X4 and X7 to form a lactam bridge include:
  • X4 is Dpr and X7 is Glu
  • X4 is Dab and X7 is Glu;
  • X4 is Orn and X7 is Glu.
  • X4 is Glu and X7 is Lys
  • X4 is Glu and X7 is Dpr; X4 is Glu and X7 is Orn; or
  • X4 is Glu and X7 is Dab.
  • X4 is Glu and X7 is Dab.
  • the location of the amide bond in the lactam bridge may affect the potency of the compound, as described above for X2 and X11.
  • Suitable pairings of residues at positions X4 and X7 in which the location of the amide bond in the lactam bridge is closer to position X7 than position X4 once formed include:
  • X4 is Orn and X7 is Glu;
  • X4 is Glu and X7 is Dpr.
  • suitable pairings of residues at positions X4 and X7 in which location of the amide bond in the lactam bridge is closer to position X4 than position X7 include:
  • X4 is Dpr and X7 is Glu
  • X4 is Glu and X7 is Lys;
  • X4 is Glu and X7 is Orn.
  • Suitable pairings of residues at positions X4 and X7 in which the side chain at position X4 is longer than the side chain at position X7, such that the location of the amide bond in the lactam bridge is closer to position 7 (X7) than position 4 (X4) once formed include:
  • X4 is Orn and X7 is Glu;
  • X4 is Glu and X7 is Dpr.
  • suitable pairings of residues at positions X4 and X7 in which the side chain at position X4 is shorter than the side chain at position X7, such that the location of the amide bond in the lactam bridge is closer to position 4 (X4) than position 7 (X7) once formed include:
  • X4 is Dpr and X7 is Glu
  • X4 is Glu and X7 is Lys;
  • X4 is Glu and X7 is Orn.
  • the length of the lactam bridge after formation of the amide bond is 5, 6, 7, 8, 9, or 10 atoms; such as 6, 7, 8, or 9 atoms; such as 7 or 8 atoms.
  • the length of the lactam bridghe after formation of the amide bond is 5, 6, or 7 atoms.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 5 atoms.
  • a suitable pairing of residues at positions X4 and X7 in which the lactam bridge has a length of 5 atoms include Dpr and Glu.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 6 atoms.
  • a suitable pairing of residues at positions X4 and X7 in which the lactam bridge has a length of 6 atoms include Dab and Glu.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 7 atoms.
  • a suitable pairing of residues at positions X4 and X7 in which the lactam bridge has a length of 7 atoms include Orn and Glu.
  • the length of the lactam bridge after formation of the amide bond (not including any atoms in the peptide backbone) is 8 atoms.
  • Suitable pairings of residues at positions X4 and X7 in which the lactam bridge has a length of 8 atoms include: Glu and Lys; Aad and Orn; and Asp and hLys.
  • Bridge containing a triazole ring The compound of the invention may comprise a bridge containing a triazole ring formed between the amino acid residues at positions X4 and X7.
  • the bridge containing a triazole ring definitions, such as suitable amino acid residues, as described above for X2 and X11 are applicable here, replacing X2 and X11 for X4 and X7.
  • positions X4 and X7 will be discussed by reference to the residues nominally present before triazole formation.
  • one of the residues at position X4 and X7 is selected from Lys(Na) and Aha, and the other is Pra.
  • X4 is Lys(Na) and X7 is Pra. In some embodiments, X4 is Aha and X7 is Pra.
  • Suitable pairings of residues at positions X4 and X7 to form a bridge containing a triazole ring include:
  • X4 is Lys(Na) and X7 is Pra; or
  • X4 is Aha and X7 is Pra.
  • X4 is the alkyne component and X7 is the azide component.
  • the location of the triazole in the bridge containing a triazole ring may affect the potency of the compound, as described above for X2 and X11.
  • Suitable pairings of residues at positions X4 and X7 in which the location of the triazole in the bridge containing a triazole ring is closer to position X7 than position X4 once formed include X4 is Lys(Na) and X7 is Pra. Alternatively in some embodiments, the location of the triazole in the bridge containing a triazole ring is closer to position X4 than position X7 once formed.

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US18/715,410 US20250154198A1 (en) 2021-12-01 2022-12-01 Peptide inhibitors of interleukin-23 receptor
CA3240982A CA3240982A1 (en) 2021-12-01 2022-12-01 Peptide inhibitors of interleukin-23 receptor
MX2024006556A MX2024006556A (es) 2021-12-01 2022-12-01 Inhibidores de peptido del receptor de interleucina-23.
IL313185A IL313185A (en) 2021-12-01 2022-12-01 Peptide inhibitors of the interleukin-23 receptor
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WO2025051920A1 (en) * 2023-09-08 2025-03-13 Sanofi New peptides as selective il-23 receptor inhibitors
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WO2024246269A1 (en) 2023-06-01 2024-12-05 Zealand Pharma A/S Peptide inhibitors of interleukin-23 receptor
WO2025051920A1 (en) * 2023-09-08 2025-03-13 Sanofi New peptides as selective il-23 receptor inhibitors
WO2026013260A1 (en) 2024-07-12 2026-01-15 Zealand Pharma A/S Peptide inhibitors of interleukin-23 receptor

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