GLUCAGON ANALOGUES

• US 20130157935A1
• Filed: 06/23/2011
• Published: 06/20/2013
• Est. Priority Date: 06/23/2010
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Meier, Eddi, Riber, Ditte, Daugaard, Jens Rosengren, Skovgaard, Marie
• Granted Patent: US 9,403,894 B2
• Time in Patent Office: Days
• US Class Current: 514/5.3
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• 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 without affecting glycemic control. 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;

2. A compound according to claim 1 having the sequence

3. A compound according to claim 1, wherein said lipophilic substituent is attached to the amino acid residue at position 16, 17, 20, 27 or 28.

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

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

6. A compound according to claim 1, having the sequence

7. A compound according to claim 1 wherein one or more of the amino acid side chains in the compound is conjugated to a polymeric moiety.

8. A compound according to claim 7 wherein one or more of the amino acid side chains in peptide X is conjugated to a polymeric moiety.

9. A composition comprising a compound according to claim 1, or a salt or derivative thereof, in admixture with a carrier.

10. A composition according to claim 9 wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.

12. 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 1.

13. 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 1.

14. A method of treating 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 1.

15. A method of treatment and/or prevention of obesity, morbid obesity, morbid obesity prior to surgery, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or 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 1.

16. The method according to claim 13 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

17. The method according to claim 16, 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, or melanin concentrating hormone receptor 1 antagonist.

18. The method according to claim 16 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

19. The method according to claim 16 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or and/or a cholesterol absorption inhibitor.

20. The method according to claim 14 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

21. The method according to claim 20, 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, or melanin concentrating hormone receptor 1 antagonist.

22. The method according to claim 20 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

23. The method according to claim 20 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.

24. The method according to claim 15 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.

25. The method according to claim 24, 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, or melanin concentrating hormone receptor 1 antagonist.

26. The method according to claim 24 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

27. The method according to claim 24 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.

11. (canceled)