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

• US 7,238,670 B2
• Filed: 10/18/2002
• Issued: 07/03/2007
• Est. Priority Date: 10/18/2001
• Status: Active Grant

• 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:
  US10/273,975
• Publication Number:
  US 20030195157A1
• Time in Patent Office: 1,719 Days
• Field of Search: 514/2, 514 13- 15, 530/300, 530/326, 530/327
• US Class Current: 514/1.9
• 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 comprising the amino acid sequence of SEQ ID NO:

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

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, gilmepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, plogiltazone, troglitazone, rosiglitazone, insulin, farglitizar, isagiltazone, regiltizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazoiidin-2-yl) methyl]phenoxy}but-2-ene, rosiglitazone, 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.

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-pyridyl)oxy]-2-hydropropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzsnesulfonemide, sibutramine, topiramate, axokine, dexamphetamine, phentermine. phenylpropanolamine 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 (LPL) 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-methylethy)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. The isolated polypeptide of claim 1 wherein said 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, 297-455, and 457-517.

11. A pharmaceutical composition comprising a polypeptide of claim 10, and a pharmaceutically acceptable carrier.

12. A pharmaceutical combination comprising a polypeptide of claim 10 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.

13. The combination of claim 12 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-I, insulin and a meglitinide.

14. The combination of claim 13 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, gilmepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, plogiltazone, troglitazone, rosiglitazone, insulin, farglitizar, isagiltazone, regiltizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazoiidin-2-yl) methyl]phenoxy}but-2-ene, rosiglitazone, 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.

15. The combination of claim 12 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.

16. The combination of claim 15 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-pyridyl)oxy]-2-hydropropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzsnesulfonemide, sibutramine, topiramate, axokine, dexamphetamine, phentermine. phenylpropanolamine and mazindol.

17. The combination of claim 12 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.

18. The combination of claim 17 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-methylethy)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).

19. 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, 297-455, and 457-517.

20. A pharmaceutical composition comprising a polypeptide of claim 19, and a pharmaceutically acceptable carrier.

21. A pharmaceutical combination comprising a polypeptide of claim 19 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.

22. The combination of claim 21 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-I (GLP-I), insulin and a meglitinide.

23. The combination of claim 22 wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, gilmepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, plogiltazone, troglitazone, rosiglitazone, insulin, farglitizar, isagiltazone, regiltizar, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazoiidin-2-yl) methyl]phenoxy}but-2-ene, rosiglitazone, 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.

24. The combination of claim 21 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.

25. The combination of claim 24 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-pyridyl)oxy]-2-hydropropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzsnesulfonemide, sibutramine, topiramate, axokine, dexamphetamine, phentermine. phenylpropanolamine and mazindol.

26. The combination of claim 21 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.

27. The combination of claim 26 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-methylethy)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).