Modified GLP-1 peptides with increased biological potency

1. A GLP-1 peptide having the following formula, or a pharmaceutically acceptable salt thereof:

X-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Y (SEQ ID NO.1)

wherein:

X is a rigidifying hydrophobic acyl moiety as obtained from the corresponding carboxylic acid of general structure I:

wherein R1 is 2- or 3-lower alkoxy, 2- or 3-hydroxy, 2- or 3- amino, 2-N-phenylamino, 2,6-dihalo or 2,3,4,5,6-pentahalo and n=0 or 1, and Y is selected from the group consisting of OH, NH 2 and Gly-OH.

2. A composition comprising a therapeutically effective amount of a peptide of claim 1 , or a pharmaceutically acceptable salt thereof, in association With at least one constituent selected from the group consisting of pharmaceutically acceptable carrier, diluent, and excipient.

3. The composition of claim 2 , wherein said therapeutically effective amount is comprised between about 1 mcg and about 10 mg.

4. A method for treating or preventing a disease or condition associated with a disorder of glucose metabolism comprising administering to a subject in need thereof a therapeutically effective amount of the peptide of claim 1 .

5. The method of claim 4 , wherein said disease or condition associated with a disorder of glucose metabolism is selected from diabetes mellitus of Type I or Type II and insulin resistance.

6. The method of claim 5 , wherein said condition is diabetes mellitus of Type I or Type II.

7. The method of claim 5 , wherein said condition is insulin resistance.

8. The method of claim 4 , wherein said disease or condition is a weight disorder or associated condition.

9. The method of claim 8 , wherein said weight disorder or associated condition is selected from at least one of lowering weight, increasing satiety, post-prandially increasing plasma insulin levels, reducing blood glucose levels, and increasing pancreatic beta cell mass in said subject.

10. The method of claim 9 , wherein said lowering weight is from about 1 to about 10 kg.

11. The method of claim 9 , wherein said increasing satiety is of the order of about 10%.

12. The method of claim 9 , wherein said post-prandially increasing plasma insulin levels is of the order of about 10%.

13. The method of claim 9 , wherein said reducing blood glucose levels is of the order of about 10%.

14. The method of claim 9 , wherein said increasing pancreatic beta cell mass is of at least about 10%.

15. The method of claim 4 , wherein said peptide, or pharmaceutically acceptable salt thereof, is administered to said subject through an administration route selected from the group consisting of subcutaneous, intravenous, transdermal, oral, buccal and intranasal.

16. The method of claim 4 , wherein said subject is a human.

17. A composition comprising a prophylactically effective amount of a peptide of claim 1 , or a pharmaceutically acceptable salt thereof, in association with at least one constituent selected from the group consisting of pharmaceutically acceptable carrier, diluent and excipient.

18. The peptide of claim 1 wherein:

R1=2-hydroxy and n=0,

R1=2-ethoxy and n=0,

R1=3-methoxy and n=1,

R1=3-amino and n=1,

R1=2-N-phenylamino and n=0,

R1=2,6-difluoro and n=1, or

R1=2,3,4,5,6-pentafluoro and n=1.

19. The peptide of claim 1 wherein the corresponding carboxylic acid is selected from the group consisting of

20. The peptide of claim 1 wherein the corresponding carboxylic acid is

and Y is NH 2 .

21. The peptide of claim 1 wherein the corresponding carboxylic acid is

and Y is Gly-OH.

22. The peptide of claim 1 wherein the corresponding carboxylic acid is

and Y is Gly-OH.

23. The peptide of claim 1 wherein the corresponding carboxylic acid is

and Y is NH 2 .