Claims
- 1. A GLP-1 compound comprising the amino acid sequence of formula 1 (SEQ ID NO: 1)
- 2. A GLP-1 compound comprising the amino acid sequence of formula II (SEQ ID NO: 2):
- 3. A GLP-1 compound comprising the amino acid sequence of formula III (SEQ ID NO: 3):
- 4. The GLP-1 compound of any one of claims 1, 2 or 3 wherein no more than 6 amino acids in the GLP-1 compound differ from the corresponding amino acid in GLP-1(7-37)OH or GLP-1-(7-36)NH2.
- 5. The GLP-1 compound of claim 4 wherein no more than 5 amino acids in the GLP-1 compound differ from the corresponding amino acid in GLP-1(7-37)OH or GLP-1(7-36)NH2.
- 6. The GLP-1 compound of claim 5 wherein no more than 4 amino acids in the GLP-1 compound differ from the corresponding amino acid in GLP-1(7-37)OH or GLP-1(7-36)NH2.
- 7. The GLP-1 compound of claim 6 wherein no more than 3 amino acids in the GLP-1 compound differ from the corresponding amino acid in GLP-1(7-37)OH or GLP-1(7-36)NH2.
- 8. The GLP-1 compound of claim 7 wherein no more than 2 amino acids in the GLP-1 compound differ from the corresponding amino acid in GLP-1(7-37)OH or GLP-1(7-36)NH2.
- 9. The GLP-1 compound of any one of claims 1 through 8 wherein Xaa8 is glycine or valine.
- 10. The GLP-1 compound of any one of claims 4 through 8 wherein Xaa8 is glycine or valine and Xaa30 is alanine, glutamic acid, aspartic acid, serine, or histidine.
- 11. The GLP-1 compound of claim 10 wherein Xaa30 is glutamic acid.
- 12. The GLP-1 compound of any one of claims 4 through 8 wherein Xaa8 is glycine or valine and Xaa37 is histidine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, serine, threonine, arginine, or lysine.
- 13. The GLP-1 compound of claim 12 wherein Xaa37 is histidine.
- 14. The GLP-1 compound of any one of claims 4 through 8 wherein Xaa8 is glycine or valine and Xaa22 is aspartic acid, glutamic acid, glutamine, asparagine, lysine, arginine, cysteine, or cysteic acid.
- 15. The GLP-1 compound of claim 14 wherein Xaa22 is aspartic acid, glutamic acid, lysine, or arginine.
- 16. The GLP-1 compound of claim 15 wherein Xaa22 is glutamic acid.
- 17. The GLP-1 compound of any one of claims 4 through 7 wherein Xaa8 is glycine or valine, Xaa22 is glutamic acid or lysine, and Xaa23 is glutamic acid or lysine.
- 18. The GLP-1 compound of any one of claims 4 through 7 wherein Xaa8 is glycine or valine, Xaa22 is glutamic acid and Xaa27 is alanine.
- 19. A glucagon-like peptide-1 (GLP-1) compound having an amino acid other than alanine at position 8 and an amino acid other than glycine at position 22.
- 20. The GLP-1 compound of claim 19, wherein said GLP-1 compound comprises no more than 3 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)NH2, or a fragment thereof in addition to the amino acids at positions 8 and 22.
- 21. The GLP-1 compound of claim 20, wherein said GLP-1 compound comprises no more than 2 amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)NH2, or a fragment thereof in addition to the amino acids at positions 8 and 22.
- 22. The GLP-1 compound of claim 21, wherein said GLP-1 compound comprises no more than 1 amino acid that differs from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)NH2, or a fragment thereof in addition to the amino acids at positions 8 and 22.
- 23. The GLP-1 compound of any one of claims 20 through 22, wherein the amino acids that differ from the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)NH2, or a fragment thereof are a conservative substitution of the corresponding amino acid in GLP-1(7-37)OH, GLP-1(7-36)NH2, or a fragment thereof.
- 24. The GLP-1 compound of any one of claims 19 through 23 wherein the side chain of the amino acid at position 22 comprises at least two carbon atoms and a polar or charged functional group.
- 25. The GLP-1 compound of any one of claims 19 through 23 wherein:
a) the amino acid at position 8 is glycine, valine, leucine, isoleucine, methionine, serine, threonine, cysteine, aspartic acid, glutamic acid, lysine, arginine, asparagine, glutamine, phenylalanine, tyrosine, histidine or tryptophan; and b) the amino acid at position 22 is aspartic acid, glutamic acid, lysine, arginine, asparagine, glutamine or histidine.
- 26. The glucagon-like peptide-1 (GLP-1) compound of any one of claims 19 through 23 wherein the amino acid at position 22 has a straight or branched chain alkyl side chain comprising two to six carbon atoms and substituted with a charged functional group.
- 27. The GLP-1 compound of claim 26 wherein the amino acid at position 22 is aspartic acid, glutamic acid, lysine or arginine.
- 28. The GLP-1 compound of any one of claims 19 through 23 wherein the amino acid at position 8 is glycine, valine, leucine, isoleucine, serine, threonine or methionine.
- 29. The GLP-1 compound of claim 28 wherein the amino acid at position 8 is glycine or valine.
- 30. The GLP-1 compound of any one of claims 19 through 23 having an amino acid with a side chain comprising a sulfonic acid group at position 22.
- 31. The GLP-1 compound of claim 29 wherein the amino acid with a side chain is cysteic acid and wherein the amino acid at position 8 is not alanine.
- 32. A GLP-1 compound comprising the amino acid sequence of SEQ ID NO: 4:
- 33. The GLP-1 compound of claim 32 wherein Xaa8 is glycine, valine, leucine, isoleucine, serine or threonine.
- 34. The GLP-1 compound of claim 33 wherein Xaa22 is lysine, aspartic acid, glutamic acid or arginine.
- 35. The GLP-1 compound of claim 34 wherein Xaa7 is L-histidine, Xaa8 is glycine or valine and R is Gly (OH).
- 36. The GLP-1 compound of claim 34 wherein the GLP-1 compound is selected from the group consisting of: a) Val8-Glu22-GLP-1(7-37)OH (SEQ ID NO: 5); b) Val8-Asp22-GLP-1(7-37)OH (SEQ ID NO: 6); c) Val8-Arg22-GLP-1(7-37)OH (SEQ ID NO: 7); and d) Val8-Lys22-GLP-1(7-37)OH (SEQ ID NO: 8).
- 37. The GLP-1 compound of claim 34 wherein the GLP-1 compound is selected from the group consisting of: a) Gly8-Glu22-GLP-1(7-37)OH (SEQ ID NO: 9); b) Gly8-Asp22-GLP-1(7-37)OH (SEQ ID NO: 10); c) Gly8-Arg22-GLP-1(7-37)OH (SEQ ID NO: 11); and d) Gly8-Lys22-GLP-1(7-37)OH (SEQ ID NO: 12).
- 38. The GLP-1 compound of any one of claims 1-37 wherein said GLP-1 compound is complexed with a divalent metal cation.
- 39. The GLP-1 compound of claim 38 wherein said GLP-1 compound is complexed with divalent zinc cation.
- 40. A method of stimulating the GLP-1 receptor in a subject in need of such stimulation, said method comprising the step of administering to the subject an effective amount of the GLP-1 compound of any one of claims 1-39.
- 41. The method of claim 40 wherein the subject is being treated for non-insulin dependent diabetes.
- 42. The method of claim 41 wherein the subject is being treated prophylactically for non-insulin dependent diabetes.
- 43. The method of claim 40 wherein the subject is being treated for obesity, stroke, myocardial infarction, catabolic changes after surgery, or irritable bowel syndrome.
- 44. The use of a GLP-1 compound as claimed in any one of claims 1 through 39 for the preparation of a medicament for the treatment of non-insulin dependent diabetes.
- 45. The use of a GLP-1 compound as claimed in any one of claims 1 through 39 for the preparation of a medicament for the treatment of obesity, stroke, myocardial infarction, catabolic changes after surgery, or irritable bowel syndrome.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/212,171, filed Jun. 16, 2000 and U.S. Provisional Application No. 60/240,349, filed Oct. 13, 2000.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US01/16474 |
6/1/2001 |
WO |
|