GLUCAGON ANALOGUES

• US 20150111817A1
• Filed: 10/16/2014
• Published: 04/23/2015
• Est. Priority Date: 10/17/2013
• Status: Active Grant

• Current Assignee: 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, HAMPRECHT, Dieter Wolfgang, RIBER, Ditte
• Granted Patent: US 9,988,429 B2
• Time in Patent Office: Days
• US Class Current: 514/5.3
• 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: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 9/00 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 materials and methods for the treatment of obesity and excess weight, diabetes, and other associated metabolic disorders. In particular, the invention provides novel glucagon analogue peptides effective in such methods. The peptides may mediate their effect by having increased selectivity for the GLP-1 receptor as compared to human glucagon.

Claims

1. A compound having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H (i.e. hydrogen), C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide having the sequence;

2. A compound according to claim 1 wherein X17 is ψ

.

3. A compound according to claim 2 wherein the compound contains one and only one residue ψ

, which is present at position 17.

4. A compound according to claim 1 wherein peptide X has a sequence selected from:

5. A compound according to claim 4 which is selected from:

6. A compound according to claim 3 wherein peptide X has a sequence selected from:

7. A compound according to claim 6 which is selected from:

42. A compound according to any one of the preceding claims wherein, when ψ

is present, the lipophilic substituent has the formula Z¹ wherein Z¹ is a lipophilic moiety conjugated directly to the side chain of the residue ψ

, or Z¹Z² where Z¹ is a lipophilic moiety, Z² is a spacer, and Z¹ is conjugated to the side chain of the residue ψ

via Z².

43. A compound according to claim 42 wherein the amino acid component of ψ

is Lys.

44. A composition comprising a compound according to any one of claims 1 to 43 in admixture with a carrier.

45. A composition according to claim 44 wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

46. A compound according to any one of claims 1 to 43 for use in a method of medical treatment.

47. A compound according to any one of claims 1 to 43 for use in a method of preventing weight gain or promoting weight loss in an individual in need thereof.

48. A compound according to any one of claims 1 to 43 for use in a method of lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof.

49. A compound according to any one of claims 1 to 43 for use in a method of treatment of a condition caused or characterised by excess body weight.

50. A compound according to any one of claims 1 to 43 for use in a method of prevention or treatment of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, diabetes, metabolic syndrome, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease.

51. A compound for use according to any one of claims 47 to 50 wherein the compound is administered as part of a combination therapy together with an agent for treatment of diabetes, obesity, dyslipidemia or hypertension.

52. A compound for use according to claim 51 wherein the agent for treatment of diabetes is a biguanide (e.g. metformin), a sulfonylurea, a meglitinide or glinide (e.g. nateglinide), a DPP-IV inhibitor, an SC31:

12 inhibitor, a glitazone, a different GLP-1 agonist, an insulin or an insulin analogue.

53. A compound for use according to claim 51, wherein the agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY receptor agonist or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, melanin concentrating hormone receptor 1 antagonist, phentermine, a combination of phentermine and topiramate, a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g. a combination of bupropion and naltrexone), or a serotonergic agent.

54. A compound for according to claim 51 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

55. A compound for use according to claim 51 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin and/or a cholesterol absorbtion inhibitor.

56. A nucleic acid encoding the amino acid sequence X or X—

Z of a compound according to any of claims 1 to 43.

57. An expression vector comprising the nucleic acid sequence of claim 56.

58. A host cell comprising the nucleic acid of claim 56 or the expression vector of claim 57 and capable of expressing and optionally secreting a compound having the amino acid sequence X or X—

Z.

59. A therapeutic kit comprising a compound according to any of claims 1 to 43 or a composition according to claim 44 or 45.

60. A method of synthesis of a compound according to any one of claims 1 to 43.

61. A method of producing a compound according to any one of claims 1 to 43, the method comprising culturing a host cell according to claim 58 under conditions suitable for expressing the peptide sequence X or X—

Z and purifying the compound thus produced.

62. A method of producing a compound according to any one of claims 1 to 43, the method comprising expressing a peptide sequence containing one or more differences from the sequence X or X—

Z in a host cell, optionally purifying the compund thus produced, and adding or modifying one or more amino acids to produce the compound.

63. A method according to claim 61 or claim 62 comprising modifying the sequence X or X—

Z to introduce one or more lipophilic and/or polymeric moieties.

8. A compound having the formula:

R¹—

X—

Z—

R²

wherein

R¹ is H (i.e. hydrogen), C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide having the sequence;

9. A compound according to claim 8 wherein ψ

is present at one of X16, X17, X20, X24 and X28.

10. A compound according to claim 9 wherein ψ

is present at only one of X16, X17, X20, X24 and X28.

11. A compound according to any one of claims 8 to 10 wherein:

X1 is His;

X2 is selected from D-Ser, Ala, D-Ala, Abu, Pro, Ac3c, Ac4c and AcSc;

X3 is selected from Gln and His;

X16 is selected from Glu, Lys and ψ

;

X17 is selected from Lys, Arg and ψ

;

X18 is selected from Ala and Arg;

X20 is selected from Lys and ψ

;

X24 is selected from Glu, Lys and ψ

;

X28 is selected from Ser, Lys and ψ

;

X29 is Ala.

12. A compound according to claim 11 wherein ψ

is present at one of X16, X17, X24 and X28.

13. A compound according to claim 12 wherein ψ

is present at only one of X16, X17, X20 and X24.

14. A compound according to any one of claims 11 to 13 wherein:

X1 is His;

X2 is selected from Ala, D-Ala, Abu and Pro ;

X3 is Gln;

X16 is selected from Glu and ψ

;

X17 is selected from Lys and ψ

;

X18 is Ala;

X20 is selected from Lys and ψ

;

X24 is selected from Glu and ψ

;

X28 is selected from Ser and ψ

;

X29 is Ala.

15. A compound according to claim 14 wherein peptide X has a sequence selected from:

16. A compound according to claim 15 which is selected from:

17. A compound according to claim 14 wherein peptide X has a sequence selected from:

18. A compound according to claim 17 which is selected from:

19. A compound according to any one of claims 8 to 10 wherein:

X1 is His;

X2 is selected from Ac3c, Ac4c and AcSc;

X3 is selected from Gln and His;

X16 is selected from Glu, Lys and ψ

;

X17 is selected from Lys, Arg and ψ

;

X18 is selected from Ala and Arg;

X20 is selected from Lys and ψ

;

X24 is selected from Glu, Lys and ψ

;

X28 is selected from Ser, Lys and ψ

;

X29 is Ala.

20. A compound according to claim 19 wherein peptide X has a sequence selected from:

21. A compound according to claim 20 which is selected from:

22. A compound according to claim 19 wherein peptide X has a sequence selected from:

23. A compound according to claim 22 which is selected from:

24. A compound according to any one of claims 8 to 10 wherein:

X1 is His;

X2 is Aib;

X3 is Gln;

X15 is selected from Asp and Glu;

X16 is selected from Glu, Lys and ψ

;

X17 is Arg;

X18 is Ala;

X20 is selected from Lys, His and ψ

;

X24 is selected from Glu, Lys and ψ

;

X28 is selected from Ser and ψ

;

X29 is Ala.

25. A compound according to claim 24 wherein one of X16 and X24 is Lys or ψ

and the other is Glu.

26. A compound according to claim 24 or claim 25 wherein X15 is Glu and X16 is Lys or ψ

.

27. A compound according to any one of claims 24 to 26 wherein peptide X has a sequence selected from:

28. A compound according to claim 27 which is selected from:

29. A compound according to any one of claims 24 to 26 wherein peptide X has a se-auence selected from:

30. A compound according to claim 29 which is selected from:

31. A compound according to any one of claims 8 to 10 wherein:

X1 is Tyr;

X2 is Aib;

X3 is Gln;

X16 is selected from Glu and ψ

;

X17 is selected from Lys and ψ

;

X18 is Ala

X20 is selected from Lys and ψ

;

X24 is selected from Glu and ψ

;

X28 is selected from Ser and ψ

;

X29 is Ala.

32. A compound according to claim 31 wherein peptide X has the sequence:

33. A compound according to claim 32 which is:

34. A compound according to claim 31 wherein peptide X has the sequence:

35. A compound according to claim 34 which is:

36. A compound according to any one of claims 8 to 10 wherein X28 and X29 are both Glu.

37. A compound according to claim 36 wherein:

X1 is His;

X2 is Aib;

X3 is Gln

X16 is selected from Glu and ψ

;

X17 is selected from Lys and ψ

;

X18 is selected from Ala and ψ

;

X20 is selected from Lys and ψ

;

X24 is selected from Glu and ψ

;

X28 is Glu;

X29 is Glu.

38. A compound according to claim 37 wherein peptide X has the sequence:

39. A compound according to claim 38 which is:

40. A compound according to claim 37 wherein peptide X has the sequence:

41. A compound according to claim 40 which is: