GLUCAGON ANALOGUES

• US 20150080295A1
• Filed: 03/03/2014
• Published: 03/19/2015
• Est. Priority Date: 12/15/2008
• Status: Abandoned Application

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Riber, Ditte, Skovgaard, Marie, Larsen, Bjarne Due, Daugaard, Jens Rosengren, MEIER, Eddi
• Application Number:
  US14/195,533
• Publication Number:
  US 20150080295A1
• 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 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 3/08 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 invention provides materials and methods for promoting weight loss or preventing weight gain, and in the treatment of diabetes, metabolic syndrome and associated 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, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

X is a peptide which has the formula I;

3. A compound according to claim 1 wherein X differs from formula I at up to 4 of the following positions whereby, if different from formula I:

the residue at position 2 is selected from;

Aib, D-Ser;

the residue at position 16 is selected from;

Arg, His, Lys, Glu, Gly;

the residue at position 24 is selected from;

Gln, Leu, Ala, Lys, Arg;

the residue at position 27 is selected from;

Met, Cys, Lys, Arg, Glu;

the residue at position 28 is selected from;

Asn, Ser, Lys, Glu, Ala, Leu; and

the residue at position 29 is selected from;

Thr, Glu, Lys.

4. A compound according to claim 1 wherein X comprises one or more of the following sets of residues:

17-Lys, 18-Ala;

17-Leu, 18-Ala;

17-Lys, 18-Ala, 20-His;

17-Leu, 18-Ala, 20-His;

17-Lys, 18-Ala, 24-Glu;

17-Leu, 18-Ala, 24-Glu;

17-Lys, 18-Ala, 27-Leu;

17-Leu, 18-Ala, 27-Leu;

17-Lys, 18-Ala, 29-Ala;

17-Leu, 18-Ala, 29-Ala;

17-Lys, 18-Ala, 27-Leu, 29-Ala;

17-Leu, 18-Ala, 27-Leu, 29-Ala;

17-Lys, 18-Ala, 27-Leu, 28-Arg, 29-Ala;

17-Leu, 18-Ala, 27-Leu, 28-Arg, 29-Ala;

24-Glu, 28-Arg;

24-Glu, 28-Arg, 27-Leu;

24-Glu, 28-Arg, 27-Leu, 29-Ala;

27-Leu, 28-Arg, 29-Ala;

29-Ala;

20-Arg, 24-Arg, 27-Lys, 28-Leu;

17-Arg;

18-Arg;

20-Gln;

24-Gln;

27-Met, 28-Asn, 29-Thr;

or

24-Lys.

6. A compound according to claim 1 wherein X has a sequence selected from the group consisting of:

8. A compound according to claim 1 wherein R¹ is H.

9. A compound according to claim 1 wherein R² is NH₂.

10. A compound according to claim 1 wherein Z has no more than 25% sequence identity with the corresponding portion of the IP-1 sequence of human oxyntomodulin having the sequence Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala.

11. A compound according to claim 1 wherein Z has a Cys as the C-terminal residue.

12. A compound according to claim 1 wherein Z is absent.

13. A compound according to claim 1 wherein one or more of the amino acid side chains in the compound, for example in the peptide X, is conjugated to a lipophilic substituent or a polymeric moiety.

14. A compound according to claim 13 wherein X has the sequence:

15. A nucleic acid encoding a compound according to claim 1.

16. The nucleic acid according to claim 15, which is comprised in an expression vector.

17. A host cell comprising a nucleic acid according to claim 15.

18. A pharmaceutical composition comprising a compound according to claim 1, in admixture with pharmaceutically acceptable carrier.

19. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a compound according to claim 1.

20. A pharmaceutical composition comprising a nucleic acid according to claim 15, in admixture with pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a host cell according to claim 17, in admixture with pharmaceutically acceptable carrier.

22. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a nucleic acid according to claim 15.

23. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a cell according to claim 17.

2. 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 I;

5. A compound according to claim 2 wherein X comprises one of the following sets of residues:

20-Gln, 24-Gln, 27-Met, 28-Asn, 29-Thr;

or 17-Leu, 20-Gln, 24-Gln, 28-Asn, 29-Thr.

7. A compound according to claim 2 wherein X has a sequence selected from the group consisting of:

24. A compound according to claim 2 wherein R¹ is H.

25. A compound according to claim 2 wherein R² is NH₂.

26. A compound according to claim 2 wherein one or more of the amino acid side chains in the compound, for example in the peptide X, is conjugated to a lipophilic substituent or a polymeric moiety.

27. A nucleic acid encoding a compound according to claim 2.

28. A nucleic acid according to claim 27, which is comprised in an expression vector.

29. A host cell comprising a nucleic acid according to claim 27.

30. A pharmaceutical composition comprising a compound according to claim 2, in admixture with pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising a nucleic acid according to claim 27, in admixture with pharmaceutically acceptable carrier.

32. A pharmaceutical composition comprising a host cell according to claim 29, in admixture with pharmaceutically acceptable carrier.

33. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a compound according to claim 2.

34. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a nucleic acid according to claim 27.

35. A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a cell according to claim 29.