N-TERMINALLY MODIFIED GLP-1 RECEPTOR MODULATORS
First Claim
1. An isolated polypeptide comprising a sequence of Formula I:
-
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11+TMFormula I wherein, Xaa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole or thiazole ring, such as histidine or thiazolylalanine;
wherein any of the carbon atoms of said amino acid are optionally substituted with hydrogen with one or more alkyl groups, or with one or more halo groups;
wherein the free amino group of said amino acid may be replaced with a hydroxyl or alkoxy group or is optionally substituted with, alkyl, acyl, benzoyl, alkyloxycarbonyl, methyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl;
and wherein the amino group of Xaa1 is optionally absent, such that Xaa1 is des-amino acid of histidine or thiazolylalanine in which any of the carbon atoms are optionally substituted with alkyl, halo, or hydroxyl groups;
Xaa2 is naturally or nonnaturally occurring amino acid selected from the group consisting of α
-amino-isobutyric acid (Aib);
(L)-alanine, D-Alanine, N-methyl-L-Alanine, N-methyl-D-Alanine, (L)-proline, (S)-α
-methyl-proline [α
-Me-Pro], (L)-azetidine (Azt), (S)-α
-methyl-azetidine (α
-Me-Azt), (L)-valine, and (R)- or (S)-isovaline, and wherein the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa3 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example aspartic acid or glutamic acid; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa4 is glycine;
Xaa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine, (L)-allo-threonine, (L)-serine, (L)-norvaline, (L)-norleucine; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa6 is a naturally or nonnaturally occurring amino acid comprising an alpha carbon which is disubstituted;
wherein one of the side chains of said amino acid contains an aromatic or heteroaromatic ring, for example alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, and alpha-methyl-2,6-difluorophenylalanine, wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more halo groups;
Xaa7 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which is substituted with a hydroxyl group, for example L-threonine or L-allo-threonine;
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl or halo groups;
Xaa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine, L-histidine and L-asparagine;
wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or halo groups;
Xaa9 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example L-aspartic acid or L-glutamic acid;
wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl or halo groups;
Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II, III, or IV;
wherein R3, R4 and R6 are each selected from the group consisting of hydrogen, alkyl, methyl, ethyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;
and wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N;
Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IIa, IIIa, or IVa;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkylcarboxamide (NR1R2);
wherein each of R1 and R2 is an alkyl or arylalkyl group;
wherein R3a, R4a and R6a are each selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;
wherein R7 is selected from the group consisting of hydrogen, methyl, and ethyl;
wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N; and
wherein Xaa11 is not an amino acid of Formula IIa when Xaa10 is an amino acid of Formula II.
1 Assignment
0 Petitions
Accused Products
Abstract
The subject matter described herein provides novel human glucagon-like peptide-1 (GLP-1) receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. The described compounds include chemically modified peptides that may stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The disclosed and claimed peptides show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.
56 Citations
62 Claims
-
1. An isolated polypeptide comprising a sequence of Formula I:
-
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11+TMFormula Iwherein, Xaa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole or thiazole ring, such as histidine or thiazolylalanine;
wherein any of the carbon atoms of said amino acid are optionally substituted with hydrogen with one or more alkyl groups, or with one or more halo groups;
wherein the free amino group of said amino acid may be replaced with a hydroxyl or alkoxy group or is optionally substituted with, alkyl, acyl, benzoyl, alkyloxycarbonyl, methyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl;
and wherein the amino group of Xaa1 is optionally absent, such that Xaa1 is des-amino acid of histidine or thiazolylalanine in which any of the carbon atoms are optionally substituted with alkyl, halo, or hydroxyl groups;
Xaa2 is naturally or nonnaturally occurring amino acid selected from the group consisting of α
-amino-isobutyric acid (Aib);
(L)-alanine, D-Alanine, N-methyl-L-Alanine, N-methyl-D-Alanine, (L)-proline, (S)-α
-methyl-proline [α
-Me-Pro], (L)-azetidine (Azt), (S)-α
-methyl-azetidine (α
-Me-Azt), (L)-valine, and (R)- or (S)-isovaline, and wherein the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa3 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example aspartic acid or glutamic acid; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa4 is glycine;
Xaa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine, (L)-allo-threonine, (L)-serine, (L)-norvaline, (L)-norleucine; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;
Xaa6 is a naturally or nonnaturally occurring amino acid comprising an alpha carbon which is disubstituted;
wherein one of the side chains of said amino acid contains an aromatic or heteroaromatic ring, for example alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, and alpha-methyl-2,6-difluorophenylalanine,wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups; and
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more halo groups;
Xaa7 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which is substituted with a hydroxyl group, for example L-threonine or L-allo-threonine;
wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl or halo groups;
Xaa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine, L-histidine and L-asparagine;
wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or halo groups;
Xaa9 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example L-aspartic acid or L-glutamic acid;
wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl or halo groups;
Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II, III, or IV;
wherein R3, R4 and R6 are each selected from the group consisting of hydrogen, alkyl, methyl, ethyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;
and wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N;
Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IIa, IIIa, or IVa;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkylcarboxamide (NR1R2);
wherein each of R1 and R2 is an alkyl or arylalkyl group;
wherein R3a, R4a and R6a are each selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;
wherein R7 is selected from the group consisting of hydrogen, methyl, and ethyl;
wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N; and
wherein Xaa11 is not an amino acid of Formula IIa when Xaa10 is an amino acid of Formula II. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 43, 44, 45, 46)
-
-
15. The isolated polypeptide of claim 2, wherein said naturally or nonnaturally occurring amino acid of Formula II is selected from the group consisting of 4-[(4′
- -methoxy-2′
-ethyl)-phenyl]phenylalanine;
4-[(4′
-ethoxy-2′
-ethyl)phenyl]phenylalanine;
4-[(4′
-methoxy-2′
-methyl)phenyl]phenylalanine;
4-[(4′
-ethoxy-2′
-methyl)phenyl]phenylalanine;
4-(2′
-ethylphenyl)phenylalanine;
4-(2′
-methylphenyl)phenylalanine;
4-[(3′
,5′
-dimethyl)phenyl]phenylalanine, 4-[(3′
,4′
-dimethoxy)phenyl]phenylalanine; and
4-[(2′
-ethyl-4′
-hydroxy)-phenyl]phenylalanine.
- -methoxy-2′
-
16. The isolated polypeptide of claim 1, wherein Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IVa, further defined by Formula VIa:
-
17. The isolated polypeptide of claim 1, wherein Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IVa, further defined by Formula VIIa:
-
18. The isolated polypeptide of claim 3, wherein said naturally or nonnaturally occurring amino acid of Formula III is selected from the group consisting of 4-[2′
- -(4′
-methoxy-6′
-ethyl)pyridyl]phenylalanine;
4-[2′
-(4′
-methoxy-6′
-methyl)pyridyl]-4-phenylalanine;
4-[2′
-(6′
-ethyl)pyridyl]phenylalanine;
4-[2′
-(6′
-methyl)pyridyl]phenylalanine;
4-[2′
-(3′
,5′
-dimethyl)pyridyl]phenylalanine;
4-[2′
-(4′
-methoxy-6′
-ethyl)pyridyl]phenylalanine;
4-[3′
-(4′
-methoxy-6′
-methyl)pyridyl]phenylalanine;
4-[3′
-(2′
-ethyl)pyridyl]phenylalanine; and
4-[3′
(6′
-methyl)pyridyl)phenylalanine.
- -(4′
-
19. The isolated polypeptide of claim 1, wherein said Xaa10 is a naturally or nonnaturally occurring amino acid of Formula IV.
-
20. The isolated polypeptide of claim 19, wherein said naturally or nonnaturally occurring amino acid of Formula IV is selected from the group consisting of 4-[(4′
- -methoxy-2′
-ethyl)phenyl]-3-pyridylalanine;
4-[(4′
-methoxy-2′
-methyl)phenyl]-3-pyridylalanine;
4-(2′
-ethylphenyl)-3-pyridylalanine;
4-(2′
-methylphenyl)-3-pyridylalanine;
4-[(3′
,5′
-dimethyl)phenyl]-3-pyridylalanine and 4-[(2′
-ethyl-4′
-hydroxy)phenyl]-3-pyridylalanine.
- -methoxy-2′
-
21. The isolated polypeptide of claim 1, wherein said Xaa11 is a naturally or nonnaturally occurring amino acid of said Formula IIa.
-
22. The isolated polypeptide of claim 21, wherein said naturally or nonnaturally occurring amino acid of Formula IIa is selected from the group consisting of 4-(2′
- -methylphenyl)phenylalanine;
4-(2′
-fluorophenyl)phenylalanine;
4-(2′
-chlorophenyl)phenylalanine;
4-[(3′
,4′
-dimethoxy)phenyl]phenylalanine; and
4-[(3′
,5′
-dimethyl)phenyl]phenylalanine;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1) or a dialkylcarboxamide (NR1R2), where each of R1 and R2 is an alkyl or arylalkyl group;
wherein R7 is chosen from the group consisting of hydrogen and methyl.
- -methylphenyl)phenylalanine;
-
23. The isolated polypeptide of claim 1, wherein said Xaa11 is a naturally or nonnaturally occurring amino acid of said Formula IIIa.
-
24. The isolated polypeptide of claim 23, wherein said naturally or nonnaturally occurring amino acid of Formula IIIa is selected from the group consisting of 4-[(6′
- -methyl)-2′
-pyridyl]phenylalanine;
4-[(6′
-methyl)-3′
-pyridyl]phenylalanine;
4-[(6′
-ethyl)-2′
-pyridyl)]phenylalanine; and
4-[(6′
-ethyl)-3′
-pyridyl)]phenylalanine;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1) or a dialkylcarboxamide (NR1R2), where each of R1 and R2 is an alkyl or arylalkyl group;
wherein R7 is chosen from the group consisting of hydrogen and methyl.
- -methyl)-2′
-
25. The isolated polypeptide of claim 4, wherein said naturally or nonnaturally occurring amino acid of Formula IVa is selected from the group consisting of 4-(2′
- -methylphenyl)-3-pyridylalanine;
4-(2′
-fluorophenyl)-3-pyridylalanine;
4-[(3′
,5′
-dimethyl)phenyl]-3-pyridylalanine;
4-(4′
-trifluoromethylphenyl)-3-pyridylalanine; and
4-(2′
-ethylphenyl)-3-pyridylalanine.
- -methylphenyl)-3-pyridylalanine;
-
26. The isolated polypeptide of claim 1, wherein:
-
Xaa1 is an amino acid selected from the group consisting of L-His, D-His, L-N-Methyl-His, D-N-Methyl-His, L-α
-methyl-His, D-α
-methyl-His, L-4-Thiazolylalanine, D-4-Thiazolylalanine, des-amino-His, des-amino-thiazolylalanine, 3-(1H-imidazol-4-yl)-2-methylpropanoyl, (S)-3-(1H-imidazol-4-yl)-2-hydroxypropanoyl (L-β
-imidazolelactyl);
(R)- and (S)-3-(1H-imidazol-4-yl)-2-methoxypropanoyl;
wherein if a terminal amino group is present, said terminal amino group is optionally substituted with hydrogen, alkyl, acyl, benzoyl, alkyloxycarbonyl (e.g., methyloxycarbonyl), aryloxycarbonyl, aralkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl;
Xaa2 is an amino acid selected from the group consisting of L-Ala, D-Ala, N-methyl-L-Ala, N-methyl-D-Ala, L-Pro, (S)-α
-methyl-proline [α
-Me-Pro], (L)-azetidine (Azt), (S)-α
-methyl-azetidine (α
-Me-Azt), and aminoisobutyric (Aib);
Xaa3 is an amino acid selected from the group consisting of L-Glu, L-Asp, and L-Gla;
Xaa4 is an amino acid selected from the group consisting of Gly;
Xaa5 is an amino acid selected from the group consisting of L-Thr, L-Nle, L-Nva, L-Aoc and L-allo-Thr;
Xaa6 is an amino acid selected from the group consisting of L-α
-Me-Phe, L-α
-Et-Phe, L-α
-Me-2-fluoro-Phe, L-α
-Me-3-fluoro-Phe, L-α
-Me-2,3-di-fluoro-Phe, L-α
-Me-2,6-di-fluoro-Phe, and L-α
-Me-Phe(penta-Fluoro)Xaa7 is an amino acid selected from the group consisting of L-Thr and L-allo-threonine;
Xaa8 is an amino acid selected from the group consisting of L-Ser, L-His, and L-Asn;
Xaa9 is L-Asp;
Xaa10 is a naturally or nonnaturally occurring amino acid selected from the group consisting of amino acids of Formulas II, III, and IV wherein Formula II is an amino acid selected from the group consisting of 4-[(4′
-methoxy-2′
-ethyl)phenyl]phenylalanine;
4-[(2′
-ethyl-4′
-hydroxy)phenyl]phenylalanine;
4-[(4′
-ethoxy-2′
-ethyl)phenyl]phenylalanine;
4-[(4′
-methoxy-2′
-methyl)phenyl]phenylalanine;
4-[(4′
-ethoxy-2′
-methyl)phenyl]phenylalanine;
4-(2′
-ethylphenyl)phenylalanine;
4-(2′
-methylphenyl)phenylalanine;
4-[(3′
,5′
-dimethyl)phenyl]phenylalanine and 4-[(3′
,4′
-dimethoxy)phenyl]phenylalanine;
wherein Formula III is an amino acid selected from the group consisting of 4-[2′
-(4′
-methoxy-6′
-ethyl)pyridyl]phenylalanine;
4-[2′
-(4′
-methoxy-6′
-methyl)pyridyl]-4-phenylalanine;
4-[2′
-(6′
-ethyl)pyridyl]phenylalanine;
4-[2′
-(6′
-methyl)pyridyl]phenylalanine;
4-[2′
-(3′
,5′
-dimethyl)pyridyl]phenylalanine;
4-[2′
-(4′
-methoxy-6′
-ethyl)pyridyl]phenylalanine;
4-[3′
-(4′
-methoxy-6′
-methyl)pyridyl]phenylalanine;
4-[3′
-(2′
-ethyl)pyridyl]phenylalanine; and
4-[3′
-(6′
-methyl)pyridyl)phenylalanine;
wherein Formula IV is an amino acid selected from the group consisting of 4-[(4′
-methoxy-2′
-ethyl)phenyl]-3-pyridylalanine;
4-[(4′
-methoxy-2′
-methyl)phenyl]-3-pyridylalanine;
4-(2′
-ethylphenyl)-3-pyridylalanine;
4-(2′
-methylphenyl)-3-pyridylalanine; and
4-[(3′
,5′
-dimethyl)phenyl]-3-pyridylalanine;
and Xaa11 is a naturally or nonnaturally occurring amino acid selected from the group consisting of amino acids of Formulas IIa, IIIa, and IVa;
wherein Formula IIa is an amino acid selected from the group consisting of 4′
-(2-methylphenyl)phenylalanine;
4′
-(2′
-fluorophenyl)phenylalanine; and
4-[(3′
,5′
-dimethyl)phenyl]phenylalanine;
wherein Formula IIIa is an amino acid selected from the group consisting of 4-(6′
-methyl-2′
-pyridyl)phenylalanine;
4-(6′
-methyl-2′
-pyridyl)phenylalanine;
4-(6′
-ethyl-2′
-pyridyl)phenylalanine; and
4-(6′
-ethyl-3′
-pyridyl)phenylalanine;
wherein Formula IVa is an amino acid selected from the group consisting of 4-(2′
-methylphenyl)-3-pyridylalanine;
4-(2′
-fluorophenyl-3-pyridylalanine;
4-[(3′
,5′
-dimethyl)phenyl]-3-pyridylalanine;
4-(4′
-trifluoromethylphenyl)-3-pyridylalanine; and
4-(2′
-ethylphenyl)-3-pyridylalanine;
wherein the C-terminal carbonyl carbon is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkylcarboxamide (NR1R2), where each of R1 and R2 is an alkyl or arylalkyl group;
wherein R7 is chosen from the group consisting of hydrogen and methyl, and wherein Xaa11 is not an amino acid of formula IIa when Xaa10 is an amino acid of Formula II.
-
-
27. An isolated polypeptide of claim 1, selected from the group consisting of:
-
43. An isolated polypeptide of claim 1, wherein
Xaa1 is L-Histidine and wherein the amino group of Xaa1 is unsubstituted; -
Xaa2 is selected from the following group consisting of;
Xaa3 is L-Glutamic acid or L-Histidine;
Xaa4 is Glycine;
Xaa5 is L-Threonine;
Xaa6 is selected from the following group consisting of;
Xaa7 is L-Threonine;
Xaa8 is selected from the following group consisting of;
Xaa9 is L-Aspartic acid;
Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II, wherein said naturally or nonnaturally occurring amino acid of Formula II is selected from the following group consisting of;
wherein Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IVa, wherein said naturally or nonnaturally occurring amino acid of Formula IVa is selected from the following group consisting of;
and;
R1 and R7 are selected from the group consisting of hydrogen and methyl.
-
-
44. An isolated polypeptide of claim 1, wherein Xaa1 is selected from the following group:
-
45. An isolated polypeptide of claim 1, wherein Xaa1 is:
-
46. An isolated polypeptide of claim 1, wherein Xaa1 is
-
28. An isolated polypeptide selected from the group consisting of:
-
29. An isolated polypeptide, wherein said isolated polypeptide comprises:
-
30. A pharmaceutical composition, comprising an isolated polypeptide of Formula I, or a polypeptide comprising any of the peptides of SEQ ID NOs:
- 1-157 and 159-179, and a pharmaceutically acceptable carrier thereof.
-
31. A pharmaceutical combination comprising an isolated polypeptide of Formula I or a polypeptide comprising any of the peptides of SEQ ID NOs:
- 1-157 and 159-179, 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.
- View Dependent Claims (32, 33, 34, 35, 36, 37)
- 38. 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 an isolated polypeptide of Formula I or a peptide comprising any of SEQ ID NOs 1-179.
-
41. A compound comprising the following structure:
-
42. A compound comprising the following structure:
-
47. A polypeptide comprising the sequence Thr-Ser-Asp-Bip (2-Et-4′
- -OH)-pyridylalanine (SEQ ID NO;
177), wherein said polypeptide binds and activates a GLP-1 receptor. - View Dependent Claims (48, 49, 50, 51, 52, 53)
- -OH)-pyridylalanine (SEQ ID NO;
-
54. A polypeptide comprising SEQ ID NO:
- 158.
-
55. A pharmaceutical composition, comprising an isolated polypeptide of SEQ ID NO:
- 158, and a pharmaceutically acceptable carrier thereof.
-
56. A pharmaceutical combination comprising an isolated polypeptide of SEQ ID NO:
- 158, 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.
- View Dependent Claims (57, 58, 59, 60, 61, 62)
Specification