Glucagon analogues
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 analog peptides effective in such methods. The peptides may mediate their effect by having increased selectivity for the glucagon-like peptide-1 (GLP-1) receptor as compared to human glucagon.
1. A compound having the formula
R 1 —X—R 2
wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
R 2 is OH or NH 2 ; and
X is a peptide which has the formula I:
HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-RAKDFIEWLLSA (SEQ ID NO:9)
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R 1 is H.
3. A compound according to claim 1 wherein R 2 is NH 2 .
4. A compound according to claim 1 , wherein said compound is
H-HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-RAKDFIEWLLSA-NH 2 (SEQ ID NO:9),
or a pharmaceutically acceptable salts thereof.
5. A composition comprising a compound according to claim 1 , or a salt or derivative thereof, in admixture with a carrier.
6. A composition according to claim 5 wherein the composition is a pharmaceutically acceptable composition, and the carrier is a pharmaceutically acceptable carrier.
7. 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 .
8. 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 .
9. The method according to claim 8 wherein the compound is administered as part of a combination therapy together with an agent for treatment of obesity, dyslipidemia or hypertension.
10. The method according to claim 9 , 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.
11. The method according to claim 9 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.
12. The method according to claim 9 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.
13. 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 .
14. The method according to claim 13 , wherein the condition is 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.
15. 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.
16. The method according to claim 15 , 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.
17. The method according to claim 15 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.
18. The method according to claim 15 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.
19. 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.
20. The method according to claim 19 , 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.
21. The method according to claim 19 wherein the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.
22. The method according to claim 19 wherein the agent for treatment of dyslipidaemia is a statin, a fibrate, a niacin or a cholesterol absorption inhibitor.