Amylin analogues
The present invention relates to amylin analogues and to their use in the treatment or prevention of a variety of diseases, conditions or disorders, including obesity, excess food intake and associated metabolic diseases such as diabetes. The analogues have good physical and chemical stability, good solubility, and a long duration of action, and are well suited for use in the form of a liquid formulation.
1. An amylin analogue which is a compound having the formula:
(SEQ ID NO: 89)
[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-
FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-
Hyp-NH 2
wherein an intramolecular lactam bridge is formed between the side chains of residues indicated by parentheses “( )”; and wherein [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently attached to the alpha amino group of an iso-glutamic acid linker;
or a pharmaceutically acceptable salt thereof.
2. A method of treating obesity, inhibiting weight gain, promoting weight loss, reducing food intake, and/or reducing excess body weight in a subject in need thereof, comprising administering to the subject an effective amount of an amylin analogue according to claim 1 .
3. The method of claim 2 , wherein the method comprises inhibiting weight gain, promoting weight loss, and/or reducing excess body weight in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
4. The method of claim 2 , wherein the method comprises treating obesity in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
5. The method of claim 2 , wherein the method comprises reducing food intake in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
6. The method of claim 2 , wherein the subject is suffering from diabetes.
7. The method of claim 2 , wherein the subject is suffering from hypertension.
8. The method of claim 2 , wherein the subject is suffering from dyslipidemia.
9. The method of claim 2 , wherein the subject is suffering from sleep apnea.
10. The method of claim 2 , wherein the subject is suffering from cardiovascular disease.
11. The method of claim 2 , wherein the amylin analogue is administered subcutaneously.
12. The method of claim 11 , wherein administration occurs once weekly.
13. A method of treating osteoarthritis, Prader-Willi syndrome, sleep apnea, Alzheimer's disease, diabetes, type 1 diabetes, type 2 diabetes, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease including metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), kidney failure, arteriosclerosis, (e.g. atherosclerosis), macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a diabetic complication, coronary heart disease, peripheral artery disease or stroke, and combinations thereof, in a subject in need thereof, comprising administering to the subject an effective amount of an amylin analogue according to claim 1 .
14. The method of claim 13 , wherein the method comprises treating osteoarthritis in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
15. The method of claim 13 , wherein the method comprises treating type 1 diabetes in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
16. The method of claim 13 , wherein the method comprises treating type 2 diabetes in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
17. The method of claim 13 , wherein the method comprises treating NASH in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
18. The method of claim 13 , wherein the method comprises treating Prader-Willi syndrome in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
19. The method of claim 13 , wherein the method comprises treating sleep apnea in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
20. The method of claim 13 , wherein the method comprises treating diabetic heart disease in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
21. The method of claim 20 , wherein the method comprises treating diabetic cardiomyopathy in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
22. The method of claim 20 , wherein the method comprises treating heart failure as a diabetic complication in a subject in need thereof by administering to the subject an effective amount of the amylin analogue.
23. The method of claim 13 , wherein the amylin analogue is administered subcutaneously.
24. The method of claim 23 , wherein administration occurs once weekly.
25. A method of lowering circulating LDL levels and/or increasing HDL/LDL ratio in a subject in need thereof, comprising administering to the subject an effective amount of an amylin analogue according to claim 1 .
26. The method of claim 25 , wherein the subject is obese.
27. The method of claim 25 , wherein the subject is suffering from diabetes, hypertension, sleep apnea, cardiovascular disease.
28. The method of claim 25 , wherein the subject is suffering from dyslipidemia.
29. The method of claim 25 , wherein the amylin analogue is administered subcutaneously.
30. The method of claim 29 , wherein administration occurs once weekly.