GLUCAGON ANALOGUES

• US 20130316941A1
• Filed: 12/19/2012
• Published: 11/28/2013
• Est. Priority Date: 12/23/2011
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG), Zealand Pharma A/S
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG), Zealand Pharma A/S
• Inventors: Tolborg, Jakob Lind, Riber, Ditte, Hamprecht, Dieter Wolfgang
• Application Number:
  US13/720,041
• Publication Number:
  US 20130316941A1
• Time in Patent Office: Days
• US Class Current: 514/1.9
• 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 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 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 9/00 Drugs for disorders of the cardiovascular system
• 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 invention provides glucagon analogue peptides and their use for promoting weight loss or preventing weight gain, and the treatment of obesity or excess body weight and associated conditions. The compounds may also be used to improve glycemic control and/or for the treatment of diabetes. The compounds may mediate their effect, inter alia, by having increased selectivity for the GLP-1 receptor as compared to human glucagon.

Claims

1-4. -4. (canceled)

5. A compound having the formula

R¹—

X—

Z—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the formula II;

6. A compound according to claim 5 wherein X12 is Arg.

7. A compound according to claim 5 wherein X has the formula IIa:

8. A compound according to claim 7 wherein X has the formula IIb:

9. A compound according to claim 5 wherein X has the sequence:

10. A compound according to claim 9 wherein X is:

16. A compound according to claim 5 wherein peptide X contains only one residue Y.

17. A compound according to claim 5 wherein the or each residue Y is Lys.

18. A compound according to claim 5 wherein Z is selected from Lys₃, Lys₄, Lys₅, Lys₆ and Lys₇.

19. A compound according to claim 5 wherein Z is absent.

20. A compound according to claim 5 wherein the or each Z¹ comprises a hexadecanoyl or octadecanoyl moiety.

21. A compound according to claim 20 wherein the or each lipophilic substituent is hexadecanoyl-isoGlu or octadecanoyl-iso-Glu.

22. A compound according to claim 5 wherein R¹ is H.

23. A compound according to claim 5 wherein R² is NH₂.

24. A compound according to claim 5 wherein one or more of the amino acid side chains in the compound is conjugated to a polymeric moiety.

25. A compound according to claim 24 wherein one or more of the amino acid side chains in peptide X is conjugated to a polymeric moiety.

27. A compound according to claim 5 which is:

30. A composition comprising a compound according to claim 5, or a salt or derivative thereof, in admixture with a carrier.

31. A composition according to claim 30 wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.

32. An isolated nucleic acid encoding a peptide X—

Z as defined in claim 5.

33. A vector comprising a nucleic acid according to claim 32.

34. A host cell comprising a nucleic acid according to claim 32.

36. A method of preventing weight gain or promoting weight loss in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 5.

37. A method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 5.

38. A method of treatment of a condition caused or characterised by excess body weight in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 5.

39. A method of prevention and/or treatment of a condition selected from the group consisting of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, type I diabetes, type II diabetes, gestational diabetes, metabolic syndrome, hypertension, atherogenic dyslipidemia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, and microvascular disease in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a compound according to claim 36.

40. The method of claim 39, wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity.

41. The method of claim 40, wherein the agent for treatment of obesity is selected from the group consisting of a glucagon-like peptide receptor 1 agonist, peptide YY receptor agonist or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, and melanin concentrating hormone receptor 1 antagonist.

45. The method of claim 39, wherein the compound is administered as part of a combination therapy together with an agent for treatment of dyslipidemia.

46. The method of claim 45, wherein the agent for treatment of dyslipidaemia is selected from the group consisting of a statin, a fibrate, a niacin, and a cholesterol absorption inhibitor.

47. The method of claim 38, wherein the compound is administered as part of a combination therapy together with an agent for treatment of diabetes.

48. The method of claim 47, wherein the agent for treatment of diabetes is selected from the group consisting of metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, a GLP-1 agonist, insulin, and an insulin analogue.

49. The method of claim 39, wherein the compound is administered as part of a combination therapy together with an agent for hypertension.

50. The method of claim 49, wherein the agent for treatment of hypertension is selected from the group consisting of an angiotensin-converting enzyme inhibitor, an angiotensin II receptor blocker, a diuretic, a beta-blocker, and a calcium channel blocker.

11-15. -15. (canceled)

26. (canceled)

28-29. -29. (canceled)

35. (canceled)

42-44. -44. (canceled)