N-terminally modified GLP-1 receptor modulators

• US 7,960,349 B2
• Filed: 05/25/2007
• Issued: 06/14/2011
• Est. Priority Date: 05/26/2006
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Zhu, Yeheng, Lee, Ving G., Riexinger, Douglas James, Mapelli, Claudio, Sulsky, Richard B., Ewing, William R.
• Primary Examiner(s): Kosar; Andrew D
• Assistant Examiner(s): GUDIBANDE, SATYANARAYAN R
• Application Number:
  US11/753,616
• Publication Number:
  US 20080045461A1
• Time in Patent Office: 1,481 Days
• Field of Search: None
• US Class Current: 514/21.8
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 33/32 Manganese; Compounds thereof
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/26 Glucagons
• 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 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 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 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.

Claims

1. 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.

2. The polypeptide of claim 1 wherein said polypeptide further comprises a proline.

3. The polypeptide of claim 2 wherein said proline is the second residue from the amino terminal residue and is alpha methyl proline.

4. The polypeptide of claim 1 wherein said pyridylalanine is 4-(2′

methyl phenyl) 3-pyridyl alanine.

5. The polypeptide of claim 1 wherein said polypeptide further comprises an amino terminal carbamate.

6. The polypeptide of claim 1 wherein said Thr-Ser-Asp-Bip(2-Et-4-OH)-pyridylalanine residues are at the seventh, eighth, ninth, and tenth, positions respectively, of said polypeptide and wherein position two comprises alpha methyl proline.

7. The polypeptide of claim 1 wherein said polypeptide is a peptide comprising SEQ ID NO:

158.

8. A polypeptide comprising SEQ ID NO:

158.

9. A pharmaceutical composition, comprising an isolated polypeptide of SEQ ID NO:

158, and a pharmaceutically acceptable carrier thereof.

10. 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.

11. The combination of claim 10 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 aP2inhibitor, a DPP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a SGLT-2 inhibitor, a GPR119 modulator and a meglitinide.

12. The combination of claim 11 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, CAS RN:

335149-08-1, (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-oxazoly)propyl] benzamide, 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], 8-36-glucagon-related peptide 1(octodon degas), N-[3-(1H-imidazol-4-yl)-1- oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine]-36a, and vildagliptin.

13. The combination of claim 10 wherein the anti-obesity agent is at least one agent selected from the group consisting of a CB-1antagonist or inverse agonist, a Y2receptor agonist, a Y4receptor agonist, a beta 3adrenergic 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.

14. The combination of claim 13 wherein the anti-obesity agent is at least one agent selected from the group consisting of rimonabant, MK-0364, SLV-319,orlistat, cetilistat, rafabregon, benzenesulfonamide, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]lamino]ethyl]phenyl]-4-(1-methylethyl) benzenesulfonamide, N-[4-[2[[3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl] amino]ethyl]phenyl]-4-(1-methylethyl)-(S) benzenesulfonamide CAS RN:

335149-25-2, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

15. The combination of claim 10 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.

16. The combination of claim 15 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, acetamide, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-benzamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1-(3H) isobenzofuranone, torcetrapib, and (3alpha, 4alpha, 5alpha)-4-(2-propenylcholestan-3-ol).

17. A polypeptide comprising SEQ ID NO:

160.

18. A polypeptide comprising SEQ ID NO:

162.