HUMAN GLUCAGON-LIKE PEPTIDE-1 MIMICS AND THEIR USE IN THE TREATMENT OF DIABETES AND RELATED CONDITIONS

• US 20070287670A1
• Filed: 04/25/2007
• Published: 12/13/2007
• Est. Priority Date: 10/18/2001
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lee, Ving, Bastos, Margarita, Mapelli, Claudio, Ewing, William, Bernatowicz, Michael, Natarajan, Sesha
• Application Number:
  US11/740,031
• Publication Number:
  US 20070287670A1
• Time in Patent Office: Days
• US Class Current: 514/1.900
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

Claims

1. An isolated polypeptide having a sequence of Formula I

A-X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-Y-Z-B 

 

I

wherein, X_aa1-9 is a naturally or nonnaturally occurring amino acid residue;

Y and Z are amino acid residues;

wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, heterocyclylalkyl said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group;

wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

A and B are optionally present;

wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—

C(O) (amide) group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂, or a R₄R₅N—

SO₂;

wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl;

wherein R₄ and R₅ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;

wherein the alpha-amino group of X_aa1 is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A;

wherein B is present and B is OR₁, NR₁R₂, or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol;

wherein R₁ and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.

2. The isolated polypeptide of claim 1 wherein the substitutions made at the alpha-carbon atoms of Y and Z are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.

3. The isolated polypeptide of claim 1 wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.

4. The isolated polypeptide of claim 3 wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.

5. The isolated polypeptide of claim 1 wherein X_aa1, X_aa2 and X_aa3 are N—

H or N-alkylated amino acid residues.

6. The isolated polypeptide of claim 5 wherein X_aa1, X_aa2 and X_aa3 are N—

H or N-methylated amino acid residues.

7. The isolated polypeptide of claim 1 wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl;

and wherein, the other substitution at the alpha-carbon of Z is substituted with hydrogen, methyl or ethyl.

8. The isolated polypeptide of claim 1 wherein X_aa1 is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a primary substituent selected from the group consisting of heterocyclylalkyl, heteroaryl, heteroarylalkyl and arylalkyl, said primary substituent optionally being substituted with secondary substituent selected from heteroaryl or heterocyclyl;

and in which the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa2 is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X_aa2; and

wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa3 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl; and

wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa4 is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl;

X_aa5 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa6 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl group, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa7 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group;

X_aa8 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa9 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; and

wherein A is hydrogen, an amino acid or peptide containing from about 1 to about 5 amino acid residues, an R group, an R—

C(O) amide group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂ or a R₄R₅N—

SO₂.

9. The isolated polypeptide of claim 8 wherein X_aa1 is an amino acid residue selected from the group consisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla;

X_aa2 is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S—

or R-Iva and Acc₃;

X_aa3 is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla;

X_aa4 is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp;

X_aa5 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

X_aa6 is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α

-Me-Phe, D-α

-Me-Phe, L-α

-Et-Phe, D-α

-Et-Phe, L-α

-Me-Phe(2-Fluoro), D-α

-Me-Phe(2-Fluoro), L-α

-Me-Phe(2,3-di-Fluoro), D-α

-Me-Phe(2,3-di-Fluoro), L-α

-Me-Phe(2,6-di-Fluoro), D-α

-Me-Phe(2,6-di-Fluoro), L-α

-Me-Phe(penta-Fluoro) and D-α

-Me-Phe(penta-Fluoro);

X_aa7 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer;

X_aa8 is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α

-Me-Ser; and

X_aa9 is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

10. The isolated polypeptide of claim 1 wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′

-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′

-Me), L-Bip(2-Et, 2′

-Me), L-Bip(2-Et, 2′

-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α

-Me-Bip and D-α

-Me-Bip;

Z is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et), L-Bip(2-n-Propyl,2′

-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′

-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me), L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-CH₂—

COOH), D-Bip(2-CH₂—

COOH), L-Bip(2′

-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala, L-α

-Me-Bip, D-α

-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo);

A is selected from the group consisting of H, Acetyl, β

-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl, 9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and (S)-2-Aminopropyl; and

B is selected from the group consisting of OH, NH₂, Trp-NH₂, 2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—

NH₂, 3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂, Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, β

-Ala-OH, GABA-OH and APA-OH.

11. The isolated polypeptide of claim 1 wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.

49. A pharmaceutical composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable carrier therefor.

50. A pharmaceutical combination comprising a polypeptide of claim 49 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

51. The combination of claim 50 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a GPR119 agonist, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

52. The combination of claim 51 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], benzamide, 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl], exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.

53. The combination of claim 50 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.

54. The combination of claim 53 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

55. The combination of claim 50 wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

56. The combination of claim 55 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).

57. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a polypeptide of claim 1.

58. The method of claim 57 further comprising administering, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

12. An isolated polypeptide having a sequence of Formula I

A-X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-Y-Z-B 

 

I

wherein, X_aa1-9 is a naturally or nonnaturally occurring amino acid residue;

Y and Z are amino acid residues;

wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group;

wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

A and B are optionally present;

wherein A is not present, and X_aa1 is an R group, an R—

C(O) (amide) group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂, or a R₄R₅N—

SO₂;

wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl;

wherein R₄ and R₅ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl;

wherein B is present and B is OR₁, NR₁R₂, or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol; and

wherein R₁ and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.

13. The isolated polypeptide of claim 12 wherein the substitutions upon the alpha-carbon atoms of Y and Z are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.

14. The isolated polypeptide of claim 12 wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.

15. The isolated polypeptide of claim 14 wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.

16. The isolated polypeptide of claim 12 wherein X_aa2 and X_aa3 are N—

H or N-alkylated amino acid residues.

17. The isolated polypeptide of claim 16 wherein X_aa2 and X_aa3 are N—

H or N-methylated amino acid residues.

18. The isolated polypeptide of claim 12 wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl, and wherein the other substitution at the alpha-carbon of Z is substituted with hydrogen, methyl or ethyl.

19. The isolated polypeptide of claim 12 wherein R, R₄ and R₅ are heteroarylalkyl or heterocycloalkyl, or R, R₄ and R₅ are cycloalkyl, cycloalkylalkyl, heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroaryl or heterocycle.

20. The isolated polypeptide of claim 12 wherein X_aa2 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X_aa2, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa3 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl; and

wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa4 is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl;

X_aa5 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa6 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa7 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group;

X_aa8 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and in which the other substitution at the alpha-carbon is hydrogen or alkyl; and

X_aa9 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.

21. The isolated polypeptide of claim 20 wherein X_aa2 is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S—

or R-Iva and Acc₃;

X_aa3 is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla;

X_aa4 is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp;

X_aa5 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

X_aa6 is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α

-Me-Phe, D-α

-Me-Phe, L-α

-Et-Phe, D-α

-Et-Phe, L-α

-Me-Phe(2-Fluoro), D-α

-Me-Phe(2-Fluoro), L-α

-Me-Phe(2,3-di-Fluoro), D-α

-Me-Phe(2,3-di-Fluoro), L-α

-Me-Phe(2,6-di-Fluoro), D-α

-Me-Phe(2,6-di-Fluoro), L-α

-Me-Phe(penta-Fluoro) and D-α

-Me-Phe(penta-Fluoro);

X_aa7 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer;

X_aa8 is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α

-Me-Ser; and

X_aa9 is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

22. The isolated polypeptide of claim 12 wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′

-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′

-Me), L-Bip(2-Et, 2′

-Me), L-Bip(2-Et, 2′

-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α

-Me-Bip and D-α

-Me-Bip;

Z is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Me), L-Bip(4-Me), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(4-Et), L-Bip(2-n-Propyl,2′

-Me), L-Bip(2,4-di-Me), L-Bip(2-Me, 2′

-Me), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(2,6-di-Me), L-Bip(2,4,6-tri-Me), L-Bip(2,3,4,5,-tetra-Me), L-Bip(3,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(3-NH-Ac), L-Bip(2-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(2-Phenyl), L-Bip(4-Phenyl), L-Bip(2-Fluoro), L-Bip(4-CF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-CH₂—

COOH), D-Bip(2-CH₂—

COOH), L-Bip(2′

-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe(3-Phenyl), L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(3-Pyridyl)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 2-Naphthyl-Ala, 2-Fluorenyl-Ala, L-α

-Me-Bip, D-α

-Me-Bip, L-Phe(4-NO₂) and L-Phe(4-Iodo); and

B is selected from the group consisting of OH, NH₂, Trp-NH₂, 2-NaphthylAla-NH₂, Phe(penta-Fluoro)-NH₂, Ser(Bzl)-NH₂, Phe(4-NO₂)—

NH₂, 3-PyridylAla-NH₂, Nva-NH₂, Lys-NH₂, Asp-NH₂, Ser-NH₂, His-NH₂, Tyr-NH₂, Phe-NH₂, L-Bip-NH₂, D-Ser-NH₂, Gly-OH, 1-Ala-OH, GABA-OH and APA-OH.

23. The isolated polypeptide of claim 12 wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.

24. An isolated polypeptide having a sequence of Formula I

A-X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-Y-Z-B 

 

I

wherein, X_aa1-9 is a naturally or nonnaturally occurring amino acid residue;

Y is an amino acid residue;

wherein one of the substitutions at the alpha-carbon atom of Y may independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group;

wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

A and B are optionally present;

wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—

C(O) (amide) group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂ or a R₄R₅N—

SO₂;

wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl;

wherein R₄ and R₅ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;

wherein the alpha-amino group of X_aa1 is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A;

wherein B is not present and Z is OR₁, NR₁R₂ or an amino-alcohol; and

wherein R₁ and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.

25. The isolated polypeptide of claim 24 wherein the substitutions upon the alpha-carbon atoms of Y are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.

26. The isolated polypeptide of claim 24 wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues.

27. The isolated polypeptide of claim 26 wherein B is an amino acid or peptide containing 1 to about 5 amino acid residues.

28. The isolated polypeptide of claim 24 wherein X_aa1, X_aa2 and X_aa3 are N—

H or N-alkylated amino acid residues.

29. The isolated polypeptide of claim 24 wherein X_aa1, X_aa2 and X_aa3 are N—

H or N-methylated amino acid residues.

30. The isolated polypeptide of claim 24 wherein the other substitution at the alpha-carbon of Y is substituted with hydrogen, methyl or ethyl.

31. The isolated polypeptide of claim 24 wherein X_aa1 is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a primary substituent selected from the group consisting of heterocyclylalkyl, heteroaryl, heteroarylalkyl, and arylalkyl, said primary substituent optionally being substituted with secondary substituent selected from heteroaryl or heterocyclyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa2 is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X_aa2, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa3 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa4 is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl;

X_aa5 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa6 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl group, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa7 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group;

X_aa8 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa9 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl; and

wherein A is hydrogen, an amino acid or peptide containing from about 1 to about 5 amino acid residues, an R group, an R—

C(O) (amide) group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂ or a R₄R₅N—

SO₂.

32. The isolated polypeptide of claim 24 wherein, X_aa1 is an amino acid residue selected from the group consisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-4-ThiazolylAla and D-4-ThiazolylAla;

X_aa2 is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S- or R-Iva and Acc₃;

X_aa3 is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla;

X_aa4 is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp;

X_aa5 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

X_aa6 is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α

-Me-Phe, D-α

-Me-Phe, L-α

-Et-Phe, D-α

-Et-Phe, L-α

-Me-Phe(2-Fluoro), D-α

-Me-Phe(2-Fluoro), L-α

-Me-Phe(2,3-di-Fluoro), D-α

-Me-Phe(2,3-di-Fluoro), L-α

-Me-Phe(2,6-di-Fluoro), D-α

-Me-Phe(2,6-di-Fluoro), L-α

-Me-Phe(penta-Fluoro) and D-α

-Me-Phe(penta-Fluoro);

X_aa7 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer;

X_aa8 is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α

-Me-Ser; and

X_aa9 is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

33. The isolated polypeptide of claim 24 wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′

-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′

-Me), L-Bip(2-Et, 2′

-Me), L-Bip(2-Et, 2′

-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et, 4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α

-Me-Bip and D-α

-Me-Bip; and

A is selected from the group consisting of H, Acetyl, β

-Ala, Ahx, Gly, Asp, Glu, Phe, Lys, Nva, Asn, Arg, Ser, Thr, Val, Trp, Tyr, Caprolactam, L-Bip, L-Ser(Bzl), 3-PyridylAla, Phe(4-Me), Phe(penta-Fluoro), 4-Methylbenzyl, 4-Fluorobenzyl, n-propyl, n-hexyl, cyclohexylmethyl, 6-hydroxypentyl, 2-Thienylmethyl, 3-Thienylmethyl, penta-Fluorobenzyl, 2-naphthylmethyl, 4-biphenylmethyl, 9-Anthracenylmethyl, benzyl, (S)-(2-amino-3-phenyl)propyl, methyl, 2-aminoethyl and (S)-2-Aminopropyl.

34. An isolated polypeptide of claim 24 wherein said polypeptide is a 10-mer to 15-mer and said polypeptide binds and activates a GLP-1 receptor.

35. An isolated polypeptide having a sequence of Formula I

A-X_aa1-X_aa2-X_aa3-X_aa4-X_aa5-X_aa6-X_aa7-X_aa8-X_aa9-Y-Z-B 

 

I

wherein, X_aa1-9 is a naturally or nonnaturally occurring amino acid residue;

Y is an amino acid residue;

wherein one of the substitutions at the alpha-carbon atom of Y may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a primary or secondary substituent selected from a cycloalkyl, heterocycle, aryl or heteroaryl group;

any of said secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group;

wherein, the primary or secondary substitutents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other;

wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl;

A and B are optionally present;

wherein A is not present, and X_aa1 is an R group, an R—

C(O) (amide) group, a carbamate group RO—

C(O), a urea R₄R₅N—

C(O), a sulfonamido R—

SO₂ or a R₄R₅N—

SO₂;

wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl;

wherein R₄ and R₅ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;

wherein B is not present and Z is OR₁, NR₁R₂ or an amino-alcohol; and

wherein R₁ and R₂ are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.

36. The isolated polypeptide of claim 35 wherein the substitutions upon the alpha-carbon atoms of Y are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group.

37. The isolated polypeptide of claim 35 wherein X_aa2 and X_aa3 are N—

H or N-alkylated amino acids residues.

38. The isolated polypeptide of claim 37 wherein X_aa2 and X_aa3 are N—

H or N-methylated amino acid residues.

39. The isolated polypeptide of claim 35 wherein the other substitution at the alpha-carbon of Y is substituted with methyl or ethyl.

40. The isolated polypeptide of claim 35 wherein R, R₄ and R₅ are heteroarylalkyl or heterocycloalkyl, or R, R₄ and R₅ are cycloalkyl, cycloalkylalkyl, heterocycle, aryl, arylalkyl or aryloxyalkyl substituted with heteroaryl or heterocycle.

41. The isolated polypeptide of claim 35 wherein X_aa2 is naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or cycloalkyl where the alkyl group may optionally form a ring with the nitrogen of X_aa2, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa3 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of a carboxyalkyl, bis-carboxyalkyl, sulfonylalkyl, heteroalkyl and mercaptoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa4 is a naturally or nonnaturally occurring amino acid residue in which the alpha-carbon is not substituted, or in which one of the substitutions at the alpha-carbon is selected from the group consisting of aminoalkyl, carboxyalkyl heteroarylalkyl and heterocycylalkyl;

X_aa5 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is an alkyl or hydroxyalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa6 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heterocyclealkyl, arylalkyl and heteroarylalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl;

X_aa7 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is a hydroxylalkyl group;

X_aa8 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at the alpha-carbon is selected from the group consisting of alkyl, hydroxylalkyl, heteroarylalkyl and carboxamidoalkyl, and wherein the other substitution at the alpha-carbon is hydrogen or alkyl; and

X_aa9 is a naturally or nonnaturally occurring amino acid residue in which one of the substitutions at alpha-carbon is selected from the group consisting of carboxylalkyl, bis-carboxylalkyl, carboxylaryl, sulfonylalkyl, carboxylamidoalkyl and heteroarylalkyl.

42. The isolated polypeptide of claim 41 wherein X_aa2 is an amino acid residue selected from the group consisting of L-Ala, D-Ala, L-Pro, Gly, D-Ser, D-Asn, L-N-Methyl-Ala, D-N-Methyl-Ala, L-4-ThioPro, L-Pro(t-4-OH), L-2-Pip, L-2-Azt, Aib, S—

or R-Iva and Acc₃;

X_aa3 is an amino acid residue selected from the group consisting of L-Glu, L-N-Methyl-Glu, L-Asp, D-Asp, L-His, L-Gla, L-Adp, L-Cys and L-4-ThiazolylAla;

X_aa4 is an amino acid residue selected from the group consisting of Gly, L-His, L-Lys and L-Asp;

X_aa5 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Nle, L-Met, L-Nva and L-Aoc;

X_aa6 is an amino acid residue selected from the group consisting of L-Phe, L-Tyr, L-Tyr(Bzl), Tyr(3-NO₂), L-Nle, L-Trp, L-Phe(penta-Fluoro), D-Phe(penta-Fluoro), Phe(2-Fluoro), Phe(3-Fluoro), Phe(4-Fluoro), Phe(2,3-di-Fluoro), Phe(3,4-di-Fluoro), Phe(3,5-di-Fluoro), L-Phe(2,6-di-Fluoro), Phe(3,4,5-tri-Fluoro), Phe(2-Iodo), Phe(2-OH), Phe(2-OMethyl), Phe(3-OMethyl), Phe(3-Cyano), Phe(2-Chloro), Phe(2-NH₂), Phe(3-NH₂), Phe(4-NH₂), Phe(4-NO₂), Phe(4-Methyl), Phe(4-Allyl), Phe(n-butyl), Phe(4-Cyclohexyl), Phe(4-Cyclohexyloxy), Phe(4-Phenyloxy), 2-NaphthylAla, 2-PyridylAla, L-4-ThiazolylAla, L-2-Thi, L-α

-Me-Phe, D-α

-Me-Phe, L-α

-Et-Phe, D-α

-Et-Phe, L-α

-Me-Phe(2-Fluoro), D-α

-Me-Phe(2-Fluoro), L-α

-Me-Phe(2,3-di-Fluoro), D-α

-Me-Phe(2,3-di-Fluoro), L-α

-Me-Phe(2,6-di-Fluoro), D-α

-Me-Phe(2,6-di-Fluoro), L-α

-Me-Phe(penta-Fluoro) and D-α

-Me-Phe(penta-Fluoro);

X_aa7 is an amino acid residue selected from the group consisting of L-Thr, D-Thr, L-Ser and L-hSer;

X_aa8 is an amino acid residue selected from the group consisting of L-Ser, L-hSer, L-His, L-Asn and L-α

-Me-Ser; and

X_aa9 is an amino acid residue selected from the group consisting of L-Asp, L-Glu, L-Gla, L-Adp, L-Asn and L-His.

43. The isolated polypeptide of claim 35 wherein Y is selected from the group consisting of L-Bip, D-Bip, L-Bip(2-Me), D-Bip(2-Me), L-Bip(2′

-Me), L-Bip(2-Et), D-Bip(2-Et), L-Bip(3-Et), L-Bip(4-Et), L-Bip(2-n-Propyl), L-Bip(2-n-Propyl, 4-OMe), L-Bip(2-n-Propyl,2′

-Me), L-Bip(3-Me), L-Bip(4-Me), L-Bip(2,3-di-Me), L-Bip(2,4-di-Me), L-Bip(2,6-di-Me), L-Bip(2,4-di-Et), L-Bip(2-Me, 2′

-Me), L-Bip(2-Et, 2′

-Me), L-Bip(2-Et, 2′

-Et), L-Bip(2-Me,4-OMe), L-Bip(2-Et,4-OMe), D-Bip(2-Et,4-OMe), L-Bip(3-OMe), L-Bip(4-OMe), L-Bip(2,4,6-tri-Me), L-Bip(2,3-di-OMe), L-Bip(2,4-di-OMe), L-Bip(2,5-di-OMe), L-Bip(3,4-di-OMe), L-Bip(2-Et,4,5-di-OMe), L-Bip(3,4-Methylene-di-oxy), L-Bip(2-Et, 4,5-Methylene-di-oxy), L-Bip(2-CH₂OH, 4-OMe), L-Bip(2-Ac), L-Bip(3-NH-Ac), L-Bip(4-NH-Ac), L-Bip(2,3-di-Chloro), L-Bip(2,4-di-Chloro), L-Bip(2,5-di-Chloro), L-Bip(3,4-di-Chloro), L-Bip(4-Fluoro), L-Bip(3,4-di-Fluoro), L-Bip(2,5-di-Fluoro), L-Bip(3-n-Propyl), L-Bip(4-n-Propyl), L-Bip(2-iso-Propyl), L-Bip(3-iso-Propyl), L-Bip(4-iso-Propyl), L-Bip(4-tert-Butyl), L-Bip(3-Phenyl), L-Bip(2-Chloro), L-Bip(3-Chloro), L-Bip(2-Fluoro), L-Bip(3-Fluoro), L-Bip(2-CF₃), L-Bip(3-CF₃), L-Bip(4-CF₃), L-Bip(3-NO₂), L-Bip(3-OCF₃), L-Bip(4-OCF₃), L-Bip(2-OEt), L-Bip(3-OEt), L-Bip(4-OEt), L-Bip(4-SMe), L-Bip(2-OH), L-Bip(3-OH), L-Bip(4-OH), L-Bip(2-CH₂—

COOH), L-Bip(3-CH₂—

COOH), L-Bip(4-CH₂—

COOH), L-Bip(2-CH₂—

NH₂), L-Bip(3-CH₂—

NH₂), L-Bip(4-CH₂—

NH₂), L-Bip(2-CH₂—

OH), L-Bip(3-CH₂—

OH), L-Bip(4-CH₂—

OH), L-Phe[4-(1-propargyl)], L-Phe[4-(1-propenyl)], L-Phe[4-n-Butyl], L-Phe[4-Cyclohexyl], Phe(4-Phenyloxy), L-Phe(penta-Fluoro), L-2-(9,10-Dihydrophenanthrenyl)-Ala, 4-(2-Benzo(b)furan)-Phe, 4-(4-Dibenzofuran)-Phe, 4-(4-Phenoxathiin)-Phe, 4-(2-Benzo(b)thiophene)-Phe, 4-(3-thiophene)-Phe, 4-(3-Quinoline)-Phe, 4-(2-Naphthyl)-Phe, 4-(1-Naphthyl)-Phe, 4-(4-(3,5-dimethylisoxazole))-Phe, 4-(2,4-dimethoxypyrimidine)-Phe, homoPhe, Tyr(Bzl), Phe(3,4-di-Chloro), Phe(4-Iodo), 2-Naphthyl-Ala, L-α

-Me-Bip and D-α

-Me-Bip.

44. The isolated polypeptide of claim 35 wherein such polypeptide is a 10-mer to 15-mer and such polypeptide and binds to and activates the GLP-1 receptor.

45. A method of making a polypeptide recognized by the family of B G-protein coupled receptors wherein the polypeptide mimics the activity of a polypeptide receptor agonist, said polypeptide having the formula

46. The method of claim 45 wherein the polypeptide mimics the activity of an endogenous polypeptide receptor agonist.

47. The method of claim 45 wherein the polypeptide receptor agonist is GLP-1.

48. The method of claim 45 further comprising replacing the message sequence of the polypeptide receptor agonist with a variant message sequence capable of inducing receptor mediated signal transduction.

59. A method for treating or delaying the progression or onset of diabetes or a diabetes-related condition comprising administering a therapeutically effective amount of an isolated polypeptide comprising the amino acid sequence of SEQ ID NO:

456.

60. The method of claim 59 wherein said isolated peptide is administered as a pharmaceutical composition.

61. The method of claim 59 wherein said diabetes-related condition is a condition selected from the group consisting of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis and hypertension.

62. The method of claim 59 further comprising administering, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

63. The method of claim 62 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) γ

agonist, a PPAR α

/γ

dual agonist, an adipocyte lipid binding protein (aP2) inhibitor, a dipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

64. The method of claim 63 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.

65. The method of claim 62 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.

66. The method of claim 65 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

67. The method of claim 62 wherein the lipid lowering agent is at least one agent selected from the group consisting of a microsomal triglyceride transfer protein (MTP) inhibitor, cholesterol ester transfer protein, a hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor.

68. The method of claim 67 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).

69. The method of claim 59 wherein the isolated polypeptide is selected from the group consisting of SEQ ID NOs:

1-23, 25-27, 31-32, 34-140, 142-145, 148, 150, 153-155, 157-160, 162, 164, 166, 168-227, 231-234, 236, 238-271, 276-290, 292, 294-295, 274-455, and 457-517.

70. A method for treating or delaying the progression or onset of diabetes or a diabetes-related condition comprising administering a therapeutically effective amount of an isolated polypeptide selected from the group consisting of SEQ ID NOs:

1-23, 25-27, 31-32, 34-140, 142-145, 148, 150, 153-155, 157-160, 162, 164, 166, 168-227, 231-234, 236, 238-271, 276-290, 292, 294-295, 274-455, and 457-517.

71. An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:

518 wherein said polypeptide binds and activates a GLP-1 receptor.

72. A pharmaceutical composition comprising a polypeptide of claim 71, and a pharmaceutically acceptable carrier.

73. A pharmaceutical combination comprising a polypeptide of claim 71 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

74. The combination of claim 73 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) γ

agonist, a PPAR α

/γ

dual agonist, an adipocyte lipid binding protein (aP2) inhibitor, a dipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

75. The combination of claim 74 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.

76. The combination of claim 73 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.

77. The combination of claim 76 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

78. The combination of claim 73 wherein the lipid lowering agent is at least one agent selected from the group consisting of a microsomal triglyceride transfer protein (MTP) inhibitor, cholesterol ester transfer protein, a hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor.

79. The combination of claim 78 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).

80. The isolated polypeptide of claim 71 wherein said polypeptide is selected from the group consisting of SEQ ID NOs:

24, 28, 29, 30, 33, 141, 146, 147, 149, 151, 152, 156, 161, 163, 165, 167, 228, 229, 230, 235, 237, 272, 273, 274, 275, 291, 293 and 296.

81. A pharmaceutical composition comprising a polypeptide of claim 80, and a pharmaceutically acceptable carrier.

82. A pharmaceutical combination comprising a polypeptide of claim 80 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

83. The combination of claim 82 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a GLP-1, insulin and a meglitinide.

84. The combination of claim 83 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.

85. The combination of claim 82 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.

86. The combination of claim 85 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

87. The combination of claim 82 wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

88. The combination of claim 87 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).

89. An isolated polypeptide selected from the group consisting of:

SEQ ID Nos;

24, 28, 29, 30, 33, 141, 146, 147, 149, 151, 152, 156, 161, 163, 165, 167, 228, 229, 230, 235, 237, 272, 273, 274, 275, 291, 293 and 296.

90. A pharmaceutical composition comprising a polypeptide of claim 89, and a pharmaceutically acceptable carrier.

91. A pharmaceutical combination comprising a polypeptide of claim 89 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

92. The combination of claim 91 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

93. The combination of claim 92 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy} but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], benzamide, 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl], exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin.

94. The combination of claim 91 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent.

95. The combination of claim 94 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

96. The combination of claim 92 wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

97. The combination of claim 96 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol).