Human glucagon-like-peptide-1 modulators and their use in treatment of diabetes and related conditions
First Claim
1. An isolated polypeptide comprising a polypeptide having a sequence of Formula I (SEQ ID NO:
- 1);
Xaa1—
Xaa2—
Xaa3—
Xaa4—
Xaa5—
Xaa6—
Xaa7—
Xaa8—
Xaa9—
Xaa10—
Xaa11
I wherein, Xaa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole;
wherein one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
wherein said amino acid optionally has a free amino group which is optionally substituted with alkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl; and
wherein when said free amino group is not present Xaa1 is the des-amino acid of histidine in which one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
Xaa2 is a naturally or nonnaturally occurring amino acid selected from the group consisting of D-alanine, α
-amino-isobutyric acid (Aib), N-methyl-D-alanine, N-ethyl-D-alanine, 2-methyl-azetidine-2-carboxylic acid, alpha-methyl-(L)-proline, 2-methylpiperidine-2-carboxylic acid and isovaline;
Xaa3 is a naturally or nonnaturally occurring amino acid having (1) an amino acid side chain comprising a carboxylic acid or (2) an imidazole side chain, and wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa4 is glycine;
Xaa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine and (L)-norvaline; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa6 is a naturally or nonnaturally occurring amino acid having a disubstituted alpha carbon having two side chains;
wherein at least one of said two side chains has an aromatic ring and at least one of said two chains has an alkyl group; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or one or more halo groups. Xaa7 is a naturally or nonnaturally occurring amino acid having an amino acid side chain which is substituted with a hydroxyl group; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine and L-histidine; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa9 is a naturally or nonnaturally occurring amino acid having an amino acid side chain comprising a carboxylic acid; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II;
wherein R4 is selected from the group consisting of hydrogen, alkyl, and halo;
wherein R3 and R6 are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and
wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IVa;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2);
wherein R4a is selected from the group consisting of hydrogen, alkyl, and halo;
wherein R3a and R6a are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
wherein R7 is selected from the group consisting of hydrogen, methyl, and ethyl; and
wherein X1, X2, X3 and X4 are each C or N, with the proviso that at least one of X1, X2, X3 and X4 is N;
wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and
wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy.
1 Assignment
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Accused Products
Abstract
The present invention 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. 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 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The peptides of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.
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Citations
66 Claims
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1. An isolated polypeptide comprising a polypeptide having a sequence of Formula I (SEQ ID NO:
- 1);
Xaa1—
Xaa2—
Xaa3—
Xaa4—
Xaa5—
Xaa6—
Xaa7—
Xaa8—
Xaa9—
Xaa10—
Xaa11
Iwherein, Xaa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole;
wherein one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
wherein said amino acid optionally has a free amino group which is optionally substituted with alkyl, acyl, benzoyl, L-lactyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, arylalkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl; and
wherein when said free amino group is not present Xaa1 is the des-amino acid of histidine in which one or more carbon atoms of said amino acid are optionally substituted with one or more alkyl groups;
Xaa2 is a naturally or nonnaturally occurring amino acid selected from the group consisting of D-alanine, α
-amino-isobutyric acid (Aib), N-methyl-D-alanine, N-ethyl-D-alanine, 2-methyl-azetidine-2-carboxylic acid, alpha-methyl-(L)-proline, 2-methylpiperidine-2-carboxylic acid and isovaline;
Xaa3 is a naturally or nonnaturally occurring amino acid having (1) an amino acid side chain comprising a carboxylic acid or (2) an imidazole side chain, and wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa4 is glycine;
Xaa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine and (L)-norvaline; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa6 is a naturally or nonnaturally occurring amino acid having a disubstituted alpha carbon having two side chains;
wherein at least one of said two side chains has an aromatic ring and at least one of said two chains has an alkyl group; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or one or more halo groups.Xaa7 is a naturally or nonnaturally occurring amino acid having an amino acid side chain which is substituted with a hydroxyl group; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine and L-histidine; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa9 is a naturally or nonnaturally occurring amino acid having an amino acid side chain comprising a carboxylic acid; and
wherein one or more carbon atoms of said amino acid is optionally substituted with one or more alkyl groups;
Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II;
wherein R4 is selected from the group consisting of hydrogen, alkyl, and halo;
wherein R3 and R6 are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and
wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IVa;
wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2);
wherein R4a is selected from the group consisting of hydrogen, alkyl, and halo;
wherein R3a and R6a are each independently selected from the group consisting of hydrogen, halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy;
wherein R7 is selected from the group consisting of hydrogen, methyl, and ethyl; and
wherein X1, X2, X3 and X4 are each C or N, with the proviso that at least one of X1, X2, X3 and X4 is N;
wherein the phenyl ring proximal to the beta-carbon of said amino acid is additionally optionally substituted with alkyl or halo; and
wherein the phenyl ring distal to the beta-carbon of said amino acid is additionally optionally substituted with halo, methyl, ethyl, alkyl, hydroxyl, methoxy, and alkoxy. - 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, 28, 29, 30, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)
- 1);
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19. An isolated polypeptide of claim 18, wherein:
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Xaa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α
-methyl-L-Pro and α
-aminoisobutyric (Aib);
X is fluoro;
Y is hydrogen;
Xaa8 is an amino acid selected from the group consisting of L-Ser and L-His;
R3 is ethyl;
R6 is methoxy;
R3a is selected from the group consisting of methyl and ethyl;
R6a is hydrogen; and
R7 is hydrogen.
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20. The isolated polypeptide of claim 1, wherein said polypeptide is a polypeptide of Formula VII:
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21. The isolated polypeptide of claim 20, wherein:
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R8 is selected from the group consisting of methyl, and Xaa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α
-methyl-L-Pro and aminoisobutyric acid (Aib);
X is fluoro;
Y is hydrogen;
Xaa8 is an amino acid selected from the group consisting of L-Ser and L-His;
R3 is ethyl;
R6 is methoxy;
R3a is selected from the group consisting of methyl and ethyl;
R6a is hydrogen; and
R7 is selected from the group consisting of hydrogen and methyl.
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22. The isolated polypeptide of claim 1, wherein said polypeptide is a polypeptide of Formula VIII:
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23. The isolated polypeptide of claim 22, wherein:
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R9 is selected from the group consisting of hydrogen and methyl;
Xaa2 is an amino acid selected from the group consisting of N-methyl-D-Ala, α
-methyl-L-Pro, and α
-aminoisobutyric acid (Aib);
X is fluoro;
Y is hydrogen;
Xaa8 is an amino acid selected from the group consisting of L-Ser and L-His;
R3 is ethyl;
R6 is methoxy;
R3a is selected from the group consisting of methyl and ethyl;
R6a is hydrogen;
R7 is hydrogen.
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24. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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25. An isolated polypeptide of claim 24, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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26. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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27. An isolated polypeptide of claim 1, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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28. An isolated polypeptide of claim 1, wherein said isolated polypeptide is:
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29. An isolated polypeptide of claim 28, wherein said isolated polypeptide is:
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30. An isolated polypeptide of claim 1, wherein said isolated polypeptide is:
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33. A pharmaceutical composition, comprising an isolated polypeptide of claim 1 and a pharmaceutically acceptable carrier thereof.
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34. A pharmaceutical composition comprising an isolated polypeptide of claim 1 and at least one therapeutic agent;
- wherein said therapeutic agent is 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.
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35. A pharmaceutical composition of claim 34 wherein said antidiabetic agent is 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 DPP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) analog, insulin and a meglitinide.
- agonist, a PPAR α
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36. A pharmaceutical composition of claim 34 wherein said antidiabetic agent is selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, muraglitazar, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, NVP-DPP-728A and saxagliptin.
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37. A pharmaceutical composition of claim 34, wherein said anti-obesity agent is selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, a CB-1 antagonist, a NPY-Y2 and a NPY-Y4 receptor agonist and an anorectic agent.
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38. A pharmaceutical composition of claim 34, wherein said anti-obesity agent is selected from the group consisting of orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine rimonabant (SR141716A), and mazindol.
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39. A pharmaceutical composition of claim 34, wherein said lipid lowering agent is 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, and an ACAT inhibitor.
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40. A pharmaceutical composition of claim 34, wherein said lipid lowering agent is selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414, and LY295427.
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41. 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 claim 1.
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42. A method of claim 41, further comprising the concurrent or sequential administration of a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, and an anti-atherosclerotic agent and a lipid-lowering agent.
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43. 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 pharmaceutical composition of claim 34.
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44. A method for administering a polypeptide of claim 1, comprising the parenteral administration of a formulation comprising a polypeptide of claim 1.
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45. A method for administering a polypeptide of claim 1, comprising the non-parenteral administration of a formulation comprising a polypeptide of claim 1.
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46. A method of claim 44, wherein said parenteral administration is selected from the group consisting of intravenous (IV) bolus injection, IV infusion, subcutaneous administration, intramuscular administration, intranasal administration, buccal administration, pulmonary administration and ophthalmic delivery.
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47. A method of claim 46, wherein said subcutaneous administration involves the use of an immediate or sustained release formulation.
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48. A method of claim 46, wherein said intramuscular administration involves the use of an immediate or sustained release formulation.
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49. A method of claim 44, wherein said formulation further comprises a pharmaceutically acceptable excipient selected from the group consisting of a solvent and co-solvent, a solubilizing agent, an emulsifying agent, a thickening agent, a chelating agent, an anti-oxidant, a reducing agent, an antimicrobial preservative, a buffer and pH adjusting agent, a bulking agent, a protectant and tonicity adjustor, and a special additive.
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50. A method of claim 44, wherein said formulation further comprises an encapsulated delivery system.
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31. A compound of Formula VIa:
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32. A compound of Formula VIIa:
- 51. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VI:
- 53. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VII:
- 55. An isolated polypeptide, wherein said polypeptide is a polypeptide of Formula VIII:
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57. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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58. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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59. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
-
60. An isolated polypeptide, wherein said isolated polypeptide is a compound selected from the group of compounds in the following table:
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61. An isolated polypeptide, wherein said isolated polypeptide is:
-
62. An isolated polypeptide, wherein said isolated polypeptide is:
-
63. An isolated polypeptide, wherein said isolated polypeptide is:
-
64. An isolated polypeptide, wherein said isolated polypeptide is:
-
65. An isolated polypeptide, wherein said isolated polypeptide is:
-
66. An isolated polypeptide, wherein said isolated polypeptide is:
Specification