GLUCAGON ANALOGUES

• US 20150210744A1
• Filed: 07/23/2013
• Published: 07/30/2015
• Est. Priority Date: 07/23/2012
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Riber, Ditte, Giehm, Lise
• Granted Patent: US 10,442,847 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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 present invention relates to glucagon analogues and their medical use, for example in the treatment of hypoglycaemia. In particular, the present invention relates to stable glucagon analogues suitable for use in a liquid formulation.

Claims

1. A compound having the formula I:

R¹—

Z—

R² 

 

(I)

or a pharmaceutically acceptable salt or solvate thereof;

wherein

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

R² is OH or NH₂; and

Z is an amino acid sequence deriving from the sequence of formula Ia;

His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Glu-Asn-Thr 

 

(Ia)

and further comprising at least four amino acid substitutions or deletions that are only at sequence positions selected from 2, 3, 4, 9, 10, 15, 16, 17, 20, 21, 24, 28 and 29, as follows;

X2 is selected from Aib and Ala;

X3 is selected from His, Pro, Dab(Ac), Dap(Ac) and Gln(Me);

X4 is DAla;

X9 is Glu;

X10 is selected from Val, Leu, N-Me-Tyr and N-Me-DTyr;

X15 is Glu;

X16 is selected from Aib, Lys, Glu, Leu, Val, DVal, Phe, His, Arg, Pro, DPro, N-Me-Ser and N-Me-DSer;

X17 is selected from Ala and Ser;

X20 is selected from Glu and Lys;

X21 is selected from Glu, Lys and Ser;

X24 is selected from Lys, Ser, Glu and Ala;

X28 is selected from Ser and Lys, and Glu, or is absent;

X29 is selected from Ser and Ala, or is absent;

with the proviso that Z is not selected from;

3. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein said at least four amino acid substitutions or deletions at amino acid sequence positions (designated as X) selected from 2, 3, 4, 9, 10, 15, 16, 17, 20, 21, 24, 28 and 29 of the compound of formula I are as follows:

X2 is selected from Aib and Ala;

X3 is selected from His and Pro;

X4 is DAla;

X9 is Glu;

X10 is selected from N-Me-Tyr and N-Me-DTyr;

X15 is Glu;

X16 is selected from Aib, Lys, Glu, Leu, Val, Phe, His and Arg;

X17 is selected from Ala and Ser;

X20 is selected from Glu and Lys;

X21 is selected from Glu, Lys and Ser;

X24 is selected from Lys, Ser, Glu and Ala;

X28 is selected from Ser, Glu, and Lys, or is absent;

X29 is selected from Ser and Ala, or is absent.

4. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the at least four amino acid substitutions or deletions are at amino acid sequence positions (designated by an X) selected from 2, 3, 4, 10, 15, 16, 17, 20, 21, 24, 28 and 29 of the compound of formula I, and are as follows:

X2 is Ala;

X3 is Dab(Ac), Dap(Ac) and Gln(Me);

X4 is DAla;

X10 is selected from Leu and Val;

X15 is Glu;

X16 is selected from Aib, Lys, Glu, Leu, and Val;

X17 is Ala;

X20 is selected from Glu and Lys;

X21 is selected from Glu and Ser;

X24 is selected from Lys, Ser and Glu;

X28 is selected from Ser, Glu and Lys;

X29 is Ala, or is absent.

5. The compound or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the at least four amino acid substitutions or deletions are at amino acid sequence positions (designated by an X) selected from 2, 3, 4, 16, 17, 20, 21, 24, 28 and 29 of the compound of formula I, and are as follows:

X2 is Ala;

X3 is Dab(Ac), Dap(Ac), Gln(Me) or His;

X4 is DAla;

X16 is selected from Aib, Lys, Glu;

X17 is Ala;

X20 is selected from Glu and Lys;

X21 is selected from Glu and Ser;

X24 is selected from Lys, Ser and Glu;

X28 is selected from Ser, Glu and Lys;

X29 is Ala, or is absent.

6. The compound according to any one of claims 1 to 5, wherein X17 is Ala.

7. The compound according to any one of claims 1 to 5, wherein Z is selected from the group consisting of:

8. The compound according to any one of claims 1 to 5, selected from the group consisting of:

9. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

10. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEDFVKWLEET-OH

or a pharmaceutically acceptable salt or solvate thereof.

11. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDKARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

12. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEDFVAWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

13. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDEARAKDFVEWLEKT-OH

or a pharmaceutically acceptable salt or solvate thereof.

14. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEDFVEWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

15. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSRYLESARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

16. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLESARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

17. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEEFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

18. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEDFVSWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

19. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDLSKYLDSARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

20. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

21. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDSARAEDFVKWLES-OH

or a pharmaceutically acceptable salt or solvate thereof.

22. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDEARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

23. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

24. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLESARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

25. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDLARAEDFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

26. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDKRRAEDFVSWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

27. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDVARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

28. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HAQGTFTSDYSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

29. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEEFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

30. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQ-DAla-TFTSDYSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

31. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDVSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

32. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HS-[Dab(Ac)]-GTFTSDYSKYLD-Aib-ARAESFVKWLEST-NH₂

or a pharmaceutically acceptable salt or solvate thereof.

33. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-RRAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

34. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HS-[Gln(Me)]-GTFTSDYSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

35. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDEARAKSFVEWLEKT-OH

or a pharmaceutically acceptable salt or solvate thereof.

36. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLDEARAKSFVEWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

37. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAKSFVEWLEKT-OH

or a pharmaceutically acceptable salt or solvate thereof.

38. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAESFVKWLESA-OH

or a pharmaceutically acceptable salt or solvate thereof.

39. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAESFVKWLEST-NH₂

or a pharmaceutically acceptable salt or solvate thereof.

40. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HS-[Dab(Ac)]-GTFTSDYSKYLD-Aib-ARAESFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

41. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEEFVSWLEKT-OH

or a pharmaceutically acceptable salt or solvate thereof.

42. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEKFVEWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

43. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEEFVAWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

44. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLD-Aib-ARAEEFVKWLEET-OH

or a pharmaceutically acceptable salt or solvate thereof.

45. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSQGTFTSDYSKYLE-Aib-ARAEEFVKWLEST-OH

or a pharmaceutically acceptable salt or solvate thereof.

46. The compound according to any one of claim 1, 3, 4 or 8 which is:

Hy-HSHGTFTSDYSKYLD-Aib-ARAEEFVKWLEST-NH₂

or a pharmaceutically acceptable salt or solvate thereof.

47. A nucleic acid construct encoding a compound according to any one of claims 1-46 or a peptide Z according to any one of claims 1 to 7.

49. A host cell comprising a nucleic acid construct according to claim 47 or an expression vector according to claim 48.

50. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1-46 and a pharmaceutically acceptable carrier.

51. A method of treating a disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-46, or a pharmaceutical composition according to claim 50, to the subject.

52. The method of claim 51, wherein the disease is selected from the group consisting of:

hypoglycaemia, acute hypoglycaemia, chronic hypoglycaemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, coronary heart disease, atherosclerosis, hypertension, dyslipidemia, hepatic steatosis, β

-blocker poisoning, insulinoma, and Von Gierkes disease.

53. The method of claim 52, wherein the disease or condition is hypoglycaemia.

54. The method of claim 53, wherein the hypoglycaemia is selected from the group consisting of:

diabetic hypoglycaemia, acute insulin-induced hypoglycaemia, non-diabetic hypoglycaemia, reactive hypoglycaemia, fasting hypoglycaemia, drug-induced hypoglycaemia, alcohol-induced hypoglycaemia, gastric bypass-induced hypoglycaemia, and hypoglycaemia occurring during pregnancy.

55. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-46 for use in a method of medical treatment.

56. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-46 for the treatment of hypoglycaemia, acute hypoglycaemia, chronic hypoglycaemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, coronary heart disease, atherosclerosis, hypertension, dyslipidemia, hepatic steatosis, β

-blocker poisoning, insulinoma, and Von Gierkes disease.

57. A compound or pharmaceutically acceptable salt or solvate thereof for use according to claim 56 wherein the hypoglycaemia is selected from the group consisting of:

diabetic hypoglycaemia, acute insulin-induced hypoglycaemia, non-diabetic hypoglycaemia, reactive hypoglycaemia, fasting hypoglycaemia, drug-induced hypoglycaemia, alcohol-induced hypoglycaemia, gastric bypass-induced hypoglycaemia, and hypoglycaemia occurring during pregnancy.

58. Use of a compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-46 in the preparation of a medicament for the treatment of hypoglycaemia, acute hypoglycaemia, chronic hypoglycaemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, coronary heart disease, atherosclerosis, hypertension, dyslipidemia, hepatic steatosis, β

-blocker poisoning, insulinoma, and Von Gierkes disease.

59. Use according to claim 58 wherein the hypoglycaemia is selected from the group consisting of:

diabetic hypoglycaemia, acute insulin-induced hypoglycaemia, non-diabetic hypoglycaemia, reactive hypoglycaemia, fasting hypoglycaemia, drug-induced hypoglycaemia, alcohol-induced hypoglycaemia, gastric bypass-induced hypoglycaemia, and hypoglycaemia occurring during pregnancy.

2. A compound having the formula I:

R¹—

Z—

R² 

 

(I)

or a pharmaceutically acceptable salt or solvate thereof;

wherein

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

R² is OH or NH₂; and

Z is an amino acid sequence deriving from the sequence of formula Ia;

His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Glu-Asn-Thr 

 

(Ia)

and further comprising at least four amino acid substitutions or deletions that are only at sequence positions (designated as X) selected from 2, 3, 9, 10, 15, 16, 17, 20, 21, 24, 28 and 29, as follows;

X2 is selected from Aib and Ala;

X3 is selected from His and Pro;

X9 is Glu;

X10 is selected from N-Me-Tyr and N-Me-DTyr;

X15 is Glu;

X16 is selected from Aib, Lys, Glu, Leu, Val, DVal, Phe, His, Arg, Pro, DPro, N-Me-Ser and N-Me-DSer;

X17 is selected from Ala and Ser;

X20 is selected from Glu and Lys;

X21 is selected from Glu, Lys and Ser;

X24 is selected from Lys, Ser, Glu and Ala;

X28 is selected from Ser and Lys, or is absent;

X29 is selected from Ser and Ala, or is absent;

with the proviso that Z is not selected from;

48. An expression vector comprising a nucleic acid construct according to claim 48.