WO1998020885A1 - Analogues de peptide yy et leurs utilisations - Google Patents

Analogues de peptide yy et leurs utilisations Download PDF

Info

Publication number
WO1998020885A1
WO1998020885A1 PCT/US1996/018374 US9618374W WO9820885A1 WO 1998020885 A1 WO1998020885 A1 WO 1998020885A1 US 9618374 W US9618374 W US 9618374W WO 9820885 A1 WO9820885 A1 WO 9820885A1
Authority
WO
WIPO (PCT)
Prior art keywords
arg
leu
seq
pyy
ala
Prior art date
Application number
PCT/US1996/018374
Other languages
English (en)
Inventor
Ambikaipakan Balasubramaniam
Original Assignee
University Of Cincinnati
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Cincinnati filed Critical University Of Cincinnati
Priority to JP10522501A priority Critical patent/JP2000505105A/ja
Priority to EP96942759A priority patent/EP1015007A1/fr
Priority to PCT/US1996/018374 priority patent/WO1998020885A1/fr
Priority to CA002271788A priority patent/CA2271788A1/fr
Priority to AU11598/97A priority patent/AU1159897A/en
Publication of WO1998020885A1 publication Critical patent/WO1998020885A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to peptide derivatives which are useful as therapeutic agents in the treatment of gastroenterological disorders.
  • Peptide YY is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc . Natl . Acad . Sci . 79:2514, 1982) .
  • Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the amino acid tyrosine in the peptide nomenclature) .
  • PYY has a number of central and peripheral regulatory roles with its homologous peptide neuropeptide Y (NPY) , which was originally isolated from porcine brain (Tatemoto, Proc . Natl . Acad . Sci . 79:5485, 1982). In contrast with the cellular location of PYY, NPY is present in submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol . Metab .
  • PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol . Metab . supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J . Physiol . supra) , while
  • PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week
  • porcine and human PYY are as follows : porcine PYY YPAKPEAPGEDASPEELSRYYAS RHYLNLVTRQRY ( SEQ . ID . NO .
  • the amino acid sequence for dog PYY and rat is the same as porcine PYY.
  • the present invention features novel analogs of peptide YY of the formula:
  • X is a chain of 0-5 amino acids, inclusive, the N- terminal one of which is bonded to R 2 and R 2 ;
  • Y is a chain of 0-4 amino acids, inclusive, the C- terminal one of which is bonded to R 3 and R 4 ;
  • R- L is H, C- L -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl) ,
  • C 7 -C 18 aralkyl e.g., benzyl
  • C 7 -C 18 alkaryl e.g., p-methylphenyl
  • R 2 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl),
  • C 7 -C 18 aralkyl e.g. , benzyl
  • C 7 -C 18 alkary1 e.g., p-methylpheny1
  • a 22 is an aromatic amino acid, Ala, Aib, Anb, N- Me- Ala, or is deleted
  • a 23 is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N Me- Ala, or is deleted;
  • a 24 is Leu, lie, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu, or is deleted;
  • a 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C_-C 10 alkyl group, or an aryl group) , Orn, or is deleted;
  • a 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or an aryl group) , Orn, or is deleted;
  • a 27 is an aromatic amino acid other than Tyr;
  • a 28 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or
  • a 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn;
  • a 30 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;
  • a 31 is Val, Leu, lie, Trp, Nle, Nva, Aib, Anb, or
  • N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;
  • R 3 is H, C--C-, ⁇ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl), C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl) ; and R 4 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl), C ⁇ C- ⁇ acyl (e.g., formyl, acetyl, and myristo
  • X is A 17 -A 18 -A 19 -A 20 -A 21 wherein A 17 is Cys, Leu, lie, Val, Nle, Nva, Aib, Anb, or N-Me-Leu; A 18 is Cys, Ser, Thr, N-Me-Ser, or N-Me-Thr; A 19 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C ⁇ alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; A 20 is an aromatic amino acid, or Cys; and A 21 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. In yet other preferred embodiments, Y is A 33 -
  • a 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) , Cys, or Orn;
  • a 34 is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or
  • Anb; A 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) ,
  • the compound has the formula: N- ⁇ -Ac- Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg- Tyr-NH 2 (SEQ. ID. NO. 3), H-Ala-Ser-Leu-Arg-His-Phe-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO.
  • N- ⁇ -Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH 2 SEQ. ID. NO. 5
  • N- ⁇ -Ac-Ala-Ser-Leu-Arg-His- Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 SEQ. ID. NO. 6)
  • N- ⁇ -Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH 2 SEQ. ID. NO. 7) or a pharmaceutically acceptable salt thereof.
  • the invention features novel analogs of peptide YY of the formula: R ⁇ R 3
  • N-terminal amino acid is bonded to R ⁇ and R 2 ;
  • Y is a chain of 0-4 amino acids, inclusive the C- terminal one of which is bonded to R 3 and R 4 ;
  • R ⁇ is H, C -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl
  • R 2 is H, C- L -C- L2 alkyl (e.g., methyl), C 6 -C 18 aryl
  • a 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C ⁇ -C ⁇ alkyl group, or an aryl group) ,
  • a 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C ⁇ C- ⁇ alkyl group, or an aryl group) , Orn, or is deleted;
  • a 27 is an aromatic amino acid;
  • a 28 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or N-Me-Leu;
  • a 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn;
  • a 30 is Leu, lie, Val, Trp, Nle, Nva, Aib, Anb, or
  • a 31 is Val, lie, Trp, Nva, Aib, Anb, or N-Me-Val;
  • a 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp;
  • R 3 is H, C- L -C- ⁇ alkyl (e.g., methyl), C 6 -C 18 aryl
  • phenyl e.g., phenyl, napthaleneacetyl
  • C ⁇ C- ⁇ acyl e.g., formyl, acetyl, and myristoyl
  • C 7 -C 18 aralkyl e.g., benzyl
  • C 7 -C 18 alkaryl e.g., p-methylphenyl
  • R 4 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl
  • a 27 is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip.
  • Y is A 33 -A 34 -A 35 -A 36 wherein
  • a 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn;
  • a 34 is Gin, Asn, Ala, Gly, N-Me-Gln, Aib, Cys, or
  • a 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e- NH-R (where R is H, a branched or straight chain alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; and
  • a 36 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof.
  • the compound has the formula N- ⁇ -Ac- Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 8) .
  • the invention features novel dimeric analogs of peptide YY.
  • the dimer may be formed by either including two peptides of Formula I, two peptides of Formula II, or one peptide of Formula I and one peptide of Formula II.
  • the dimer is formed by utilizing a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide.
  • a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide.
  • suitable dicarboxylic acid linkers are succinic acid, gluta ic acid, and phthalic acid.
  • the dimer is formed by utilizing an amino acid linker capable of binding to a free amine group of one peptide and a free carboxyl group of the other peptide.
  • the amino acid linker is a non ⁇ -amino acid.
  • Suitable amino acid linkers are amino-caproic acid and amino-valeric acid.
  • the dimer is formed by a disulfide bridge between cysteines located within each peptide. See, e.g., M. Berngtowicz and G. Piatsueda,
  • the invention features analogs of Formula I or Formula II having at least one pseudopeptide bond between amino acid residues.
  • pseudopeptide bond is meant that the carbon atom participating in the bond between two residues is reduced from a carbonyl carbon to a methylene carbon, i.e., CH 2 - NH; or less preferably that of CO-NH is replaced with any of CH 2 -S, CH 2 -CH 2 , CH 2 -0, or CH 2 -CO.
  • a pseudopeptide peptide bond is symbolized herein by “ ⁇ " .
  • the pseudopeptide bonds are located between one or more amino acid residues, e.g., A 28 ⁇ A 29 , A 29 ⁇ A 30 , A 30 ⁇ A 31 , A 31 ⁇ A 32 , A 32 ⁇ A 33 , A 33 ⁇ A 34 , A 34 ⁇ A 35 , or A 35 ⁇ A 36 .
  • such pseudopeptide bond analogs can be used to form dimeric analogs as is described above. A detailed discussion of the chemistry of pseudopeptide bonds is given in Coy et al. (1988) Tetrahedron 44:835-841.
  • the invention features radiolabeled analogs of Formula I and Formula II.
  • the analogs have a tyrosine iodinated on the phenyl ring at carbon position 3 or 5.
  • the radioactive iodine is preferably I 125 or I 123 .
  • R is -CH 2 COOH for Asp
  • R is -H for Gly
  • R is - CH 2 0H for Ser
  • R is -CH 3 for Ala
  • R is -CH 2 CH 2 CH 2 CH 2 NH 2 for Arg.
  • amino acid residue when optically active, it is the L-form configuration that is intended unless the D-form is expressly designated.
  • Tic tetrahydroisoquinoline-3-carboxylic acid
  • Aib aminoisobutyric acid
  • the compounds of the present invention can be provided in the form of pharmaceutically acceptable salts.
  • preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, trifluoroacetic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid and the like.
  • the invention features one of the above compounds and a pharmaceutically acceptable carrier substance in a therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion.
  • the composition is in the form of a liquid, pill, tablet, or capsule for oral administration; a liquid capable of being administered nasally as drops or spray or a liquid for intravenous, subcutaneous, parenteral, intraperitoneal or rectal administration.
  • the therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration. For maximum efficacy, zero-order release is desired.
  • the invention features, a method for decreasing excess intestinal water and electrolyte secretion in a mammal, the method comprising administering to the mammal, e.g., a human, a therapeutically effective amount of the above mentioned compounds .
  • the invention features a method of regulating cell proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the composition of the above mentioned compounds.
  • the method regulates the proliferation of an intestinal cell.
  • the invention also features methods for increasing nutrient transport, regulating lipolysis, and regulating blood flow in a mammal, the methods comprising administering to the mammal a therapeutically effective amount of the above mentioned compositions.
  • the compounds of the invention exhibit a broad range of biological activities related to their antisecretory and antimotility properties.
  • the compounds are believed to suppress gastrointestinal secretions by direct interaction with epithelial cells or, perhaps, by inhibiting secretion of hormones or neurotransmitters which stimulate intestinal secretion.
  • the compounds of the invention may also control intestinal blood flow which in turn may modulate intestinal hydrostatic pressure in favor of net water absorption.
  • the compounds of the invention are especially useful in the treatment of any number of gastrointestinal disorders (see e.g., Harrison 's Principles of Internal Medicine , McGraw-Hill Inc., New York, 12th Ed.) that are associated with excess intestinal electrolyte and water secretion as well as decreased absorption, e.g., infectious (e.g., viral or bacterial) diarrhea, inflammatory diarrhea, short bowel syndrome, or the diarrhea which typically occurs following surgical procedures, e.g., ileostomy.
  • infectious diarrhea examples include, without limitation, acute viral diarrhea, acute bacterial diarrhea (e.g., salmonella, campylobacter , and clostridium or due to protozoal infections), or traveller's diarrhea (e.g., Norwalk virus or rotavirus) .
  • infectious diarrhea examples include, without limitation, malabsorption syndrome, tropical spue, chronic pancreatitis, Crohn's disease, diarrhea, and irritable bowel syndrome.
  • the peptides of the invention can be used to treat an emergency or life-threatening situation involving a gastrointestinal disorder, e.g., after surgery or due to cholera.
  • the compounds of the invention can be used to treat patients suffering from Acquired Immune Deficiency Syndrome (AIDS) , especially during cachexia.
  • AIDS Acquired Immune Deficiency Syndrome
  • the compounds of the invention are also useful for inhibiting small intestinal fluid and electrolyte secretion, augmenting nutrient transport — as well as increasing cell proliferation — in the gastrointestinal tract, regulating lipolysis in, e.g, adipose tissue, and regulating blood flow in a mammal.
  • the compounds of the invention are advantageous because they are truncated versions of the natural PYY peptide; thus, the shorter peptide not only facilitates easier synthesis and purification of the compounds, but also improves and reduces manufacturing procedures and expenses.
  • FIG. 1 shows a semipreparative reversed phase chromatogram of N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3) ( «25mg) obtained by HF cleavage.
  • FIG. 2 shows a graph of the inhibition of 125 i- PYY binding to rat jejunal membranes by increasing concentrations of PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. NO. 10), [Im-DNP-His 26 ]PYY (SEQ. ID. NO. 9),
  • FIGS. 3A-B show the antisecretory effects of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10) and analogs up one baseline short circuit current (SCC) in voltage clamped preparation of rat jejunum. Values of changes in SCC are quoted of ⁇ A/0.6cm 2 , mean ⁇ SEM from between 3 and 7 different jejunal preparations. Peptides shown in A and B are denoted by the same symbol as in FIG. 2.
  • FIG. 4 shows a graph of the inhibition of 125 I-PYY binding to rat jejunal membranes by increasing concentrations of PYY, N- ⁇ -Ac-PYY (22-36) (SEQ. ID. NO. 14), N- ⁇ -Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25), N- ⁇ -Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO. 22), N- ⁇ -Ac- [Nal 27 ]PYY (22- 36) (SEQ. ID. NO. 23), N- ⁇ -Ac- [Bth 27 ]PYY (22-36) (SEQ. ID. NO.
  • N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3), N- ⁇ -Ac- [Phe 27 ]PYY(25-36) (SEQ. ID. NO. 26), N- ⁇ -Ac- [Trp 27 ] PYY (22- 36) (SEQ. ID. NO. 5), and N- ⁇ -Ac- [Thi 27 ]PYY (22-36) (SEQ. ID. NO. 6) .
  • the peptides of the invention have the general formula recited in the Summary of the Invention above. They all have an aromatic amino acid group at position 27 which is important for both antisecretory activity and utility as antidiarrheal compounds.
  • the peptides of the present invention may be synthesized by any techniques that are known to those skilled in the peptide art. An excellent summary of the many techniques so available may be found in Solid Phase Peptide Synthesis 2nd ed. (Stewart, J.M. and Young, J. D. Pierce Chemical Company, Rockford, IL, 1984) .
  • peptides listed in Table 1 and Table 2 were synthesized as follows. Peptide synthesis was performed on an Applied Biosystems Model 430A synthesizer. Amino acid and sequence analyses were carried out using Waters Pico-Tag and Applied Biosystems Model 470A instruments, respectively. Peptides were purified using a Waters Model 600 solvent delivery system equipped with a Model 481 Spectrophotometer and U6K injector according to standard protocols. Peptide masses were determined at the University of Michigan, Protein Chemistry Facility, Ann Arbor, Michigan according to standard methods. All Boc-L-amino acid derivatives, solvents, chemicals and the resins were obtained commercially and used without further purification.
  • Paramethylbenzhydroxyla ine (MBHA) resin (0.45 mmol, -NH 2 ) was placed in the reaction vessel of the peptide synthesizer and the protected amino acid derivatives were sequentially coupled using the program provided by the manufacturers modified to incorporate a double coupling procedure (see, e.g., Balasubramaniam et al., Peptide Research 1: 32, 1988). All amino acids were coupled using 2.2 equivalents of preformed symmetrical anhydrides. Arg, Gin and Asn, however, were coupled as preformed 1-hydroxybenzotriazole (HOBT) esters to avoid side reactions.
  • HOBT 1-hydroxybenzotriazole
  • the N- ⁇ -Boc group was removed and in some instances the free ⁇ -NH2 was acetylated by reaction with acetic anhydride (2 equivalents) and diisopropyl ethylamine until a negative ninhydrin test was obtained (Anal. Biochem. 34:595, 1970).
  • the peptide resin (-1.0 g) was then treated with HF (10 ml) containing p-cresol (-0.8 g) for 1 h at -2 to -4 °C.
  • Binding experiments were conducted in a total volume of 0.25 ml 60 mM HEPES buffer, pH 7, containing 2% BSA, 0.1% bacitracin, 5 mM MgCl 2 and 0.05 nM 125 ⁇ -p ⁇ with or without competing peptides. Bound and free peptides were separated by centrifugation at 20,000 X g for 10 min.
  • Non-specific 125 I-PYY binding was determined in the presence of 1 ⁇ M unlabeled PYY represented 10% of the total binding.
  • SCC short-circuit current
  • Preparations were automatically voltage clamped using a W-P dual voltage clamp and the SCC displayed continuously on pen recorders. Once a stable baseline SCC was reached, peptides were added to the basolateral reservoir only, and cumulative concentration-response profiles constructed. Data Analyses All points in the binding experiments are the mean of at least three experiments performed in duplicate.
  • Fig. 1 shows the RP-HPLC chromatogram of N- ⁇ -Ac- [Phe 27 ] PYY (22-36) (SEQ. ID. NO. 3).
  • the free peptides were further characterized by sequence analysis (see, Table 1 and Table 2) .
  • the overall yields of the peptides were in the range of 10% to 30%.
  • PEPTIDES RT d MH+ (Calc.) BINDING 1 " SCC L (min) IC 50 (nM) EC 5Q (nM)
  • a isocratic, 27% CH,CN containing 0.1% TFA
  • b mean of three separate experiments
  • c isocratic, 32% CH--CN containing 0.1% TFA
  • d from reference 10; n.d.: not determined
  • N- ⁇ -myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N- ⁇ - naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19) analogs in contrast to their moderate binding potency, exhibited poor antisecretory responses with threshold 5 concentrations of about 20nM and EC 50 values greater than 2 and 30 ⁇ M respectively.
  • Subsequent addition of PYY (100 nM) further l ⁇ reduced the SCC by
  • N- ⁇ -myristoyl-PYY (22-36) SEQ. ID. NO. 18
  • N- ⁇ - naphthaleneacetyl-PYY (22-36) SEQ. ID. NO. 19
  • analogs inhibited 125 I-PYY binding with moderate potency, but exhibited poor antisecretory responses. This observation suggested that these analogs may be antagonists.
  • Table 2 and Fig. 4 present the IC 50 values for additonal PYY(22-36) (SEQ. ID. NO. 10) and PYY (25-36) analogs. Based on the results presented in Table 2 the analogs in this series exhibited the following order of potency: N- ⁇ -Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25) ⁇ N- ⁇ -Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO.
  • NPY/PYY receptors characterized to date have been broadly classified into Y-l, Y-2 and Y-3 subtypes (Balsubramaniam et al. J . Biol . Chem . 265:14724, 1990; Michel, Trends Pharmacol . Sci . 12:389, 1991). Both Y-l and Y-2 receptors exhibit a preference for PYY over NPY, and more significantly C-terminal fragments of NPY and PYY are effective only at the Y-2 subtype. Y-3 receptors, on the other hand, exhibit a greater affinity for NPY than PYY. Since rat jejunal mucosa antisecretory responses show an order of agonist potency PYY (SEQ. ID.
  • an effective amount of an any one or combination of the analogs of the invention e.g. , N- ⁇ - Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3), N- ⁇ -Ac-
  • compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously) , rectally ( e.g., by suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or either solid, liquid or gaseous dosage, including tablets and suspensions.
  • the administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum.
  • the method of the present invention is practiced when relief of symptoms is specifically required or perhaps imminent.
  • the method of the present invention is effectively practiced as continuous or prophylactic treatment.
  • Useful pharmaceutical carriers for the preparation of the compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid- protein vesicles) , sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • formulation for intravenous administration comprise sterile aqueous solutions of the active ingredient (s) which are prepared by dissolving solid active ingredient (s) in water to produce an aqueous solution, and rendering the solution sterile.
  • Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • the compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like.
  • Suitable pharmaceutical carriers and their formulation are described in Remington 's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.
  • the dose of the compound of the present invention for treating the above-mentioned disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
  • Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".
  • a typical administration is oral administration or parenteral administration.
  • the daily dose in the case of oral administration is typically in the range of 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration is typically in the range of 0.001 to 50 mg/kg body weight.
  • the therapeutic agents be relatively non-toxic, non-antigenic and non-irritating at the levels in actual use.
  • Tyr Pro lie Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu
  • Xaa in position 15 is an abbreviation of N-Me-Tyr.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 6 is an abbreviation of Thi (2-thienylalanine) .
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-) .
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 26 is an abbreviation of im-DNP-His.
  • the sequence has an acetylated N- terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N- ).
  • the sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 5 is an abbreviation of p.Cl.Pro.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 15 is an abbreviation of N-Me-Tyr.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH).
  • the sequence has a myristoylated N-terminus (i.e., N- ⁇ -myristoyl) , rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • the sequence has an amide C- terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., C0- OH) .
  • Xaa in position 6 is an abbreviation of Bth.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide c-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 6 is an abbreviation of Bip.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2), rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 6 is an abbreviation of Nal.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 6 is an abbreviation of Tic.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 15 is an abbreviation of Thi.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .
  • Xaa in position 15 is an abbreviation of Thz.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH).
  • Xaa in position 6 is an abbreviation of Pep.
  • the sequence has an acetylated N-terminus (i.e., N- ⁇ -Ac), rather than an amino N-terminus (i.e., H2N-).
  • the sequence has an amide C-terminus (i.e., CO-NH2 ) , rather than a carboxyl C-terminus (i.e., CO-OH) .

Abstract

L'invention concerne des analogues de PYY ainsi que des compositions et des procédés utiles pour réguler les activités biologiques telles que la prolifération cellulaire, le transport d'éléments nutritifs, la lipolyse et la sécrétion intestinale d'eau et d'électrolyte.
PCT/US1996/018374 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations WO1998020885A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP10522501A JP2000505105A (ja) 1996-11-13 1996-11-13 ペプチドｙｙのアナログおよびその使用
EP96942759A EP1015007A1 (fr) 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations
PCT/US1996/018374 WO1998020885A1 (fr) 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations
CA002271788A CA2271788A1 (fr) 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations
AU11598/97A AU1159897A (en) 1996-11-13 1996-11-13 Analogs of peptide yy and uses thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1996/018374 WO1998020885A1 (fr) 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations

Publications (1)

Publication Number Publication Date
WO1998020885A1 true WO1998020885A1 (fr) 1998-05-22

Family

ID=22256144

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/018374 WO1998020885A1 (fr) 1996-11-13 1996-11-13 Analogues de peptide yy et leurs utilisations

Country Status (5)

Country Link
EP (1) EP1015007A1 (fr)
JP (1) JP2000505105A (fr)
AU (1) AU1159897A (fr)
CA (1) CA2271788A1 (fr)
WO (1) WO1998020885A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083926A2 (fr) 2001-04-17 2002-10-24 Cedars-Sinai Medical Center Procedes de diagnostic et de traitement de la proliferation bacterienne dans l'intestin grele et des conditions pathologiques associees
JP2003518914A (ja) * 1999-02-10 2003-06-17 キュリス インコーポレイテッド グルコース代謝障害を治療する方法および試薬
WO2004066966A2 (fr) 2003-01-17 2004-08-12 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Analogues du peptide yy
WO2006066024A2 (fr) 2004-12-13 2006-06-22 Amylin Pharmaceuticals, Inc. Motifs de famille de polypeptides pancreatiques, polypeptides et leurs methodes
US7157426B2 (en) 2002-12-17 2007-01-02 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US7166575B2 (en) 2002-12-17 2007-01-23 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
US7229966B2 (en) 2002-12-17 2007-06-12 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents
US7723471B2 (en) 2004-02-11 2010-05-25 Amylin Pharmaceuticals, Inc. Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
EP2279732A2 (fr) 2004-05-14 2011-02-02 Emisphere Technologies, Inc. Composés et compositions pour la distribution d'agents actifs
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour
KR101399178B1 (ko) 2005-08-11 2014-06-18 아스트라제네카 파마수티컬스 엘피 선별가능한 특성을 갖는 하이브리드 폴리펩티드
US9035085B2 (en) 2004-05-14 2015-05-19 Emisphere Technologies, Inc. Aryl ketone compounds and compositions for delivering active agents
US10005824B2 (en) 2015-06-12 2018-06-26 Novo Nordisk A/S Selective PYY compounds and uses thereof
US10246497B2 (en) 2013-11-15 2019-04-02 Novo Nordisk A/S Selective PYY compounds and uses thereof
US10583172B2 (en) 2013-11-15 2020-03-10 Novo Nordisk A/S HPYY(1-36) having a beta-homoarginine substitution at position 35
US11382957B2 (en) 2010-12-16 2022-07-12 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11759502B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5026685A (en) * 1988-07-15 1991-06-25 The Salk Institute For Biological Studies NPY peptide analogs
US5328899A (en) * 1988-07-15 1994-07-12 The Salk Institute For Biological Studies NPY peptide analogs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5026685A (en) * 1988-07-15 1991-06-25 The Salk Institute For Biological Studies NPY peptide analogs
US5328899A (en) * 1988-07-15 1994-07-12 The Salk Institute For Biological Studies NPY peptide analogs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNALS NEW YORK ACADEMY OF SCIENCES, 1990, Vol. 611, TATEMOTO K., "Neuropeptide Y and Its Receptor Antagonists: Use of an Analog Mixture-Screening Strategy", pages 1-5. *
PROC. NATL. ACAD. SCI. U.S.A., February 1992, Vol. 89, TATEMOTO et al., "Synthesis of Receptor Antagonists of Neuropeptide Y", pages 1174-1178. *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003518914A (ja) * 1999-02-10 2003-06-17 キュリス インコーポレイテッド グルコース代謝障害を治療する方法および試薬
US7906482B2 (en) 1999-05-17 2011-03-15 Advanced Diagnostics And Discovery Anti-obesity agents
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents
US9358276B2 (en) 1999-08-11 2016-06-07 Cedars-Sinai Medical Center Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions
WO2002083926A2 (fr) 2001-04-17 2002-10-24 Cedars-Sinai Medical Center Procedes de diagnostic et de traitement de la proliferation bacterienne dans l'intestin grele et des conditions pathologiques associees
EP2305213A2 (fr) 2001-04-17 2011-04-06 Cedars-Sinai Medical Center Traitement du développement bactérien au sein de l'intestin et de pathologies liées à celui-ci
EP2267445A1 (fr) 2001-04-17 2010-12-29 Cedars-Sinai Medical Center Procédés de détection d'un léger développement bactérien au sein de l'intestin chez un sujet humain
US8217001B2 (en) 2001-09-24 2012-07-10 Imperial Innovations Limited Modification of feeding behavior
US7459432B2 (en) 2001-09-24 2008-12-02 Imperial College Innovations Ltd. Modification of feeding behavior
US7186691B2 (en) 2002-12-17 2007-03-06 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US7166575B2 (en) 2002-12-17 2007-01-23 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
US7157426B2 (en) 2002-12-17 2007-01-02 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US7229966B2 (en) 2002-12-17 2007-06-12 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
EP2277527A3 (fr) * 2003-01-17 2011-08-31 Ipsen Pharma Analogues du peptide yy
WO2004066966A2 (fr) 2003-01-17 2004-08-12 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Analogues du peptide yy
EP1583549A2 (fr) * 2003-01-17 2005-10-12 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Analogues du peptide yy
US7811989B2 (en) 2003-01-17 2010-10-12 Ipsen Pharma S.A.S. Peptide YY analogs
EP2277527A2 (fr) 2003-01-17 2011-01-26 Ipsen Pharma Analogues du peptide YY
EP1583549A4 (fr) * 2003-01-17 2006-10-04 Sod Conseils Rech Applic Analogues du peptide yy
US7723471B2 (en) 2004-02-11 2010-05-25 Amylin Pharmaceuticals, Inc. Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US8603969B2 (en) 2004-02-11 2013-12-10 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs and polypeptides comprising the same
US8906849B2 (en) 2004-02-11 2014-12-09 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
US8426361B2 (en) 2004-02-11 2013-04-23 Amylin Pharmaceuticals, Llc Pancreatic polypeptide family motifs, polypeptides and methods comprising the same
EP2279732A2 (fr) 2004-05-14 2011-02-02 Emisphere Technologies, Inc. Composés et compositions pour la distribution d'agents actifs
US9035085B2 (en) 2004-05-14 2015-05-19 Emisphere Technologies, Inc. Aryl ketone compounds and compositions for delivering active agents
WO2006066024A3 (fr) * 2004-12-13 2007-02-01 Amylin Pharmaceuticals Inc Motifs de famille de polypeptides pancreatiques, polypeptides et leurs methodes
WO2006066024A2 (fr) 2004-12-13 2006-06-22 Amylin Pharmaceuticals, Inc. Motifs de famille de polypeptides pancreatiques, polypeptides et leurs methodes
EP2360180A2 (fr) 2004-12-13 2011-08-24 Amylin Pharmaceuticals Inc. Motifs de la famille des polypeptides pancréatiques, polypeptides, méthodes et utilisation de lesdites polypeptides
EP3000826A1 (fr) 2004-12-13 2016-03-30 Amylin Pharmaceuticals, LLC Motifs de famille de polypeptides pancreatiques, polypeptides et leurs methodes
KR101399178B1 (ko) 2005-08-11 2014-06-18 아스트라제네카 파마수티컬스 엘피 선별가능한 특성을 갖는 하이브리드 폴리펩티드
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour
US11382957B2 (en) 2010-12-16 2022-07-12 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
US11759502B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11759501B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US11759503B2 (en) 2012-03-22 2023-09-19 Novo Nordisk A/S Compositions of GLP-1 peptides and preparation thereof
US10583172B2 (en) 2013-11-15 2020-03-10 Novo Nordisk A/S HPYY(1-36) having a beta-homoarginine substitution at position 35
US10246497B2 (en) 2013-11-15 2019-04-02 Novo Nordisk A/S Selective PYY compounds and uses thereof
US10005824B2 (en) 2015-06-12 2018-06-26 Novo Nordisk A/S Selective PYY compounds and uses thereof
US11833248B2 (en) 2018-02-02 2023-12-05 Novo Nordisk A/S Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

Also Published As

Publication number Publication date
AU1159897A (en) 1998-06-03
CA2271788A1 (fr) 1998-05-22
EP1015007A1 (fr) 2000-07-05
JP2000505105A (ja) 2000-04-25

Similar Documents

Publication Publication Date Title
US5604203A (en) Analogs of peptide YY and uses thereof
US6046167A (en) Peptide YY analogs
WO1998020885A1 (fr) Analogues de peptide yy et leurs utilisations
US6242563B1 (en) Peptide analogues
JP3759748B2 (ja) 成長ホルモン放出性を有する化合物
US20100331245A1 (en) Peptide yy analogs
AU7174494A (en) Neuropeptide y antagonists and agonists
US20030050436A1 (en) Octapeptide bombesin analogs
JP2004514651A (ja) グレリン類似体
JP2002542159A (ja) メラノコルチン受容体リガンド
WO1995000542A1 (fr) Antagonistes du recepteur a la bombesine et leur utilisation
EP2161282A1 (fr) Peptides analogues de PACAP
DK2473518T3 (en) Stabilized melanocortin ligands
HU213114B (en) Process for producing nonapeptide bombesin antagonists and pharmaceutical compositions containing them
WO2006020207A2 (fr) Composes pour la regulation de l'appetit
US20070287665A1 (en) Urotensin-II agonists and antagonists
AU2002232903A1 (en) Urotensin-II agonists and antagonists
EP1878743A2 (fr) Agonistes et antagonistes de l'urotensine II

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2271788

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1996942759

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1996942759

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1996942759

Country of ref document: EP