Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions

• US 7,238,671 B2
• Filed: 04/21/2003
• Issued: 07/03/2007
• Est. Priority Date: 10/18/2001
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lee, Ving, Ewing, William R., Mapelli, Claudio, Bernatowicz, Michael, Natarajan, Sesha Iyer, Bastos, Margarita M.
• Primary Examiner(s): Tsang; Cecilia J.
• Assistant Examiner(s): Kosar; Andrew D.
• Application Number:
  US10/419,399
• Publication Number:
  US 20040127423A1
• Time in Patent Office: 1,534 Days
• Field of Search: 514/2, 514 13- 15, 530/300, 530/326, 530/327
• US Class Current: 514/4.8
• 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: 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 which binds and activates a GLP-1 receptor, said polypeptide comprising:

an amino terminus comprising a first amino acid or a des-amino group;

said amino terminus further comprising a capping moiety selected from the group consisting of acyl, lactic acid, hydroxy-acyl, urea, carbamate, and sulfonyl;

said polypeptide further comprising SEQ ID NO;

469 wherein position five of SEQ ID NO;

469 optionally terminates as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid, or an amino alcohol.

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

3. A pharmaceutical combination comprising a polypeptide of claim 1 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.

4. The combination of claim 3 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-I (GLP-I), insulin and a meglitinide.

5. The combination of claim 4 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-perhydmisoindol-2yl)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.

6. The combination of claim 3 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.

7. The combination of claim 6 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, pheniylpropanolamine and mazindol.

8. The combination of claim 3 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.

9. The combination of claim 8 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).

10. An isolated polypeptide of claim 1 selected from the group consisting of SEQ ID NOs:

456-468.

11. An isolated polypeptide selected from the group consisting of SEQ ID NOs:

456-468.

12. A pharmaceutical composition comprising a polypeptide of claim 11 and a pharmaceutically acceptable carrier.

13. A pharmaceutical combination comprising a polypeptide of claim 11 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.

14. The combination of claim 13 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, 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-I (GLP-I), insulin and a meglitinide.

15. The combination of claim 14 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, fargiltizar, 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-2yl)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.

16. The combination of claim 13 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.

17. The combination of claim 16 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, phenylprapanolamine and mazindol.

18. The combination of claim 13 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 trio acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor.

19. The combination of claim 18 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).