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1. CA2458371 - ANALOGUES DE GLP-1 (GLUCAGON-LIKE PEPTIDE 1)

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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CLAIMS
What is claimed is:
1. A GLP-1 compound comprising the amino acid sequence of formula 1 (SEQ ID NO:1)
Xaa7-Xaa8-Glu-Gly-Thr-Xaa12-Thr-Ser-Asp-Xaa16-Ser Xaa18-Xaa19-Xaa20-Glu-Xaa22-Gln-Ala-Xaa25-Lys-Xaa27 Phe-Ile-Xaa30-Trp-Leu-Xaa33-Lyb-Gly-Arg-Xaa37
Formula 1 (SEQ ID NO: 1)
wherein:
Xaa7 is: L-histidine, D-histidine, desamino-histidine, 2amino-histidine, β-hydroxy-histidine, homohistidine; α-fluoromethyl-histidine, or α methyl-histidine;
Xaa8 is: Ala,Gly, Val, Leu, Ile, Ser, or Thr;
Xaa12 is: Phe Trp , or Tyr ;
Xaal6 is: Val,Trp, Ile, Leu, Phe, or Tyr;
Xaal8 is: Ser,Trp, Tyr, Phe, Lys, Ile, Leu, or Val;
Xaal9 is: Tyr,Trp, or Phe;
Xaa20 is: Leu, Phe, Tyr, or Trp;
Xaa22 is: Gly,Glu, Asp, Lys;
Xaa25 is: Ala,Val, Ile, or Leu;
Xaa27 is: Glu,Ile, or Ala;
Xaa30 is: Ala or Glu
Xaa33 is: Val,or Ile; and
Xaa37 is: Gly,His, NH2, or is absent.
provided that the GLP-1 compound does not have the sequence of GLP-1 (7-37) OH, GLP-1 (7-36) -NH2, Gly8-GLP1 (7-37) OH, Gly8-GLP-1 (7-36) NH2, Val8-GLP-1 (7-37) OH,
Val8-GLP-1 (7-36)NH2, Lue8-GLP-1 (7-37) OH, Leu8-GLP-1 (736)NH2, Ile8-GLP-1 (7-37)OH, Ile8-GLP-1 (7-36)NH2, Ser8-
GLP-1 (7-37) OH, Ser8-GLP-1 (7-36) NH2, Thr8-GLP-1 (7-37) OH,
Thr8-GLP-1 (7-36) NH2, Val8-Tyr12-GLP-1 (7-37) OH, Val8 Tyr12-GLP-1 (7-36) NH2, Val8-Tyr16-GLP-1 (7-37) OH, Val8 Tyr16-GLP-1 (7-36) NH2, Val8-Glu22-GLP-1 (7-37) OH, Val8 Glu22-GLP-1 (7-36) NH2, Gly8-Glu22-GLP-1 (7-37) OH, Gly8G1u22-GLP-1 (7-36) NH2, Val8-Asp22-GLP-1 (7-37) OH, Val8 Asp22-GLP-1 (7-36) NH2, Gly8-Asp22-GLP-1 (7-37) OH, Gly8 Asp22-GLP-1 (7-36) NH2, Val8-Lys22-GLP-1 (7-37) OH, Val8 Lys22-GLP-1 (7-36) NH2, Gly8-Lys22-GLP-1 (7-37) OH, Gly8 Lys22-GLP-1 (7-36) NH2, Leu8-Glu22-GLP-1 (7-37) OH, Leu8 Glu22-GLP-1 (7-36) NH2, Ile8-Glu22-GLP-1 (7-37) OH, Ile8 G1u22-GLP-1 (7-36) NH2, Leu8-Asp22-GLP-1 (7-37) OH, Leu8 Asp22-GLP-1 (7-36) NH2, Ile8-Asp22-GLP-1 (7-37) OH, Ile8 Asp22-GLP-1 (7-36) NH2, Leu8-Lys22-GLP-1 (7-37) OH, Leu8 Lys22-GLP-1 (7-36) NH2, Ile8-Lys22-GLP-1 (7-37) OH, Ile8 Lys22-GLP-1 (7-36) NH2, Ser8-Glu22-GLP-1 (7-37) OH, Ser8 G1u22-GLP-1 (7-36) NH2, Thr8-G1u22-GLP-1 (7-37) OH, Thr8 Glu22-GLP-1 (7-36) NH2, Ser8-Asp22-GLP-1 (7-37) OH, Ser8 Asp22-GLP-1 (7-36) NH2, Thr8-Asp22-GLP-1 (7-37) OH, Thr8 Asp22-GLP-1 (7-36) NH2, Ser8-Lys22-GLP-1 (7-37) OH, Ser8 Lys22-GLP-1 (7-36) NH2, Thr8-Lys22-GLP-1 (7-37) OH, Thr8 Lys22-GLP-1 (7-36) NH2, G1u22-GLP-1 (7-37)OH, G1u22-GLP-1 (736)NH2, Asp22-GLP-1 (7-37)OH, Asp22-GLP-1 (7-36)NH2, Lys22 GLP-1 (7-37) OH, Lys22-GLP-1 (7-36) NH2, Val8-Ala27-GLP-1 (737) OH, Val8-G1u22-Ala27-GLP-1 (7-37) OH, Val8-Glu30-GLP1 (7-37) OH, Val8-Glu30-GLP-1 (7-36) NH2, Gly8-Glu30-GLP-1 (737) OH, Gly8-Glu30-GLP-1 (7-36)NH2, Leu8-Glu30-GLP-1 (737) OH, Leu8-Glu30-GLP-1 (7-36) NH2, Ile8-Glu30-GLP-1 (737) OH, Ile8-Glu30-GLP-1 (7-36)NH2, Ser8-Glu30-GLP-1 (737) OH, Ser8-Glu30-GLP-1 (7-36) NH2, Thr8-Glu30-GLP-1 (737) OH, Thr8-Glu30-GLP-1 (7-36) NH2, Val8-His37-GLP-1 (737) OH, Val8-His37-GLP-1 (7-36)NH2, Gly8-His37-GLP-1 (737) OH, Gly8-His37-GLP-1 (7-36)NH2, Leu8-His37-GLP-1 (737) OH, Leu8-His37-GLP-1 (7-36)NH2, Ile8-His37-GLP-1 (7-
37) OH, Ile8-His37-GLP-1 (7-36) NH2, Ser8-His37-GLP-1 (737) OH, Ser8-His37-GLP-1 (7-36) NH2, Thr8-His37-GLP-1 (737) OH, Thr8-His37-GLP-1 (7-36) NH2.
2. The GLP-1 compound of Claim 1 provided that the GLP-1 compound does not differ from GLP-1(7-37)OH or GLP-1(736)NH2 by more than 5 amino acids.
3. The GLP-1 compound of Claim 2 provided that the GLP-1 compound does not differ by more than 4 amino acids.
4. The GLP-1 compound of Claim 3 provided that the GLP-1 compound does not differ by more than 3 amino acids.
5. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, and
Xaa22 is Glu, Asp, or Lys.
6. The GLP-1 compound of Claim 5 wherein Xaa22 is Glu.
7. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, and
Xaa30 is Glu.
8. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, and
Xaa37 is His.
9. The GLP-1 compound of any one of Claims 1 through 3 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, and
Xaa22 is Glu and Xaa37 is His.
10. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is Z-histidine, Xaa8 is Val or Gly, and
Xaa22 is Glu, Asp, or Lys and Xaa16 is Tyr, Trp, Leu, or
Ile.
11. The GLP-1 compound of Claim 10 wherein Xaa22 is Glu.
12. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa16 is
Tyr, Trp, Leu, or Ile, and Xaa30 is Glu.
13. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa16 is
Tyr, Trp, Leu, or Ile, and Xaa37 is His,
14. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa22 is
Glu, Asp, or Lys and Xaa25 is Leu, Ile, or Val.
15. The GLP-1 compound of Claim 14 wherein Xaa22 is Glu.
16. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa25 is
Leu, Ile, or Val and Xaa30 is Glu.
17. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa25 is
Leu, Ile, or Val and Xaa30 is His.
18. The GLP-1 compound of any one of Claims 14, 15, 16, or 17 wherein Xaa25 is Val or Ile.
19. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa22 is
Glu, Asp, or Lys and Xaa33 is Ile.
20. ~The GLP-1 compound of Claim 19 wherein Xaa22 is Glu.
21. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa30 is
Glu and Xaa33 is Ile.
22. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa33 is
Ile, and Xaa37 is His.
23. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa22 is
Glu, Asp, or Lys and Xaa18 is Trp, Tyr, Phe, Lys, Ile,
Leu, or Val.
24. ~The GLP-1 compound of Claim 23 wherein Xaa22 is Glu.
25. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa18 is
Trp, Tyr, Phe, Lys, Ile, Leu, or Val, and Xaa30 is Glu.
26. ~The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa18 is
Trp, Tyr, Phe, Lys, Ile, Leu, or Val and Xaa37 is His.
27. ~The GLP-1 compound of any one of Claims 23, 24, 25, and 26 wherein Xaa18 is Trp, Tyr, or Ile.
28. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa22 is
Glu, Asp, or Lys and Xaa19 is Tyr, Trp, or Phe.
29. The GLP-1 compound of Claim 28 wherein Xaa22 is Glu.
30. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa19 is
Trp, Tyr, or Phe and Xaa30 is Glu.
31. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa19 is
Trp, Tyr, or Phe and Xaa37 is His.
32. A GLP-1 compound comprising the amino acid sequence of formula II (SEQ ID NO:2)
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser Xaa18-Tyr-Leu-Glu-Xaa22-Gln-Ala-Xaa25-Lys-Glu-Phe Ile-Ala-Trp-Leu-Xaa33-Lys-Gly-Arg-Xaa37
Formula II (SEQ ID NO: 2) wherein:
Xaa7 is: L-histidine, D-histidine, desamino-histidine, 2amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, or αmethyl-histidine;
Xaa8 is: Gly, Ala, Val, Leu, Ile, Ser, or Thr;
Xaa16 is: Val, Phe, Tyr, or Trp;
Xaa18 is: Ser, Tyr, Trp, Phe, Lys, Ile, Leu, or Val;
Xaa22 is: Gly, Glu, Asp, or Lys;
Xaa25 is: Ala, Val, Ile, or Leu;
Xaa33 is: Val or Ile; and
Xaa37 is: Gly, NH2, or is absent. provided that the GLP-1 compound does not have the sequence of GLP-1(7-37)OH, GLP-1(7-36)-NH2, Gly8-GLP-1(7-37)OH, Gly8-
GLP-1(7-36)NH2, Val8-GLP-1(7-37)OH, Val8-GLP-1(7-36)NH2,
Lue8-GLP-1(7-37)OH, Leu8-GLP-1(7-36)NH2, Ile8-GLP-1(7-37)OH,
Ile8-GLP-1(7-36)NH2, Ser8-GLP-1(7-37)OH, Ser8-GLP-1(7-36)NH2,
Thr8-GLP-1(7-37)OH, Thr8-GLP-1(7-36)NH2, Val8-Tyr16-GLP-1(737)OH, Val8-Tyr16-GLP-1(7-36)NH2, Val8-Glu22-GLP-1(7-37)OH,
Val8-Glu22-GLP-1(7-36)NH2, Gly8-Glu22-GLP-1(7-37)OH, Gly8 Glu22-GLP-1(7-36)NH2, Val8-Asp22-GLP-1(7-37)OH, Val8-Asp22-GLP1(7-36)NH2, Gly8-Asp22-GLP-1(7-37)OH, Gly8-Asp22-GLP-1(736)NH2, Val8-Lys22-GLP-1(7-37)OH, Val8-Lys22-GLP-1(7-36)NH2,
Gly8-Lys22-GLP-1(7-37)OH, Gly8-Lys22-GLP-1(7-36)NH2, Leu8 Glu22-GLP-1(7-37)OH, Leu8-Glu22-GLP-1(7-36)NH2, Ile8-Glu22-GLP1(7-37)OH, Ile8-Glu22-GLP-1(7-36)NH2, Leu8-Asp22-GLP-1(737)OH, Leu8-Asp22-GLP-1(7-36)NH2, Ile8-Asp22-GLP-1(7-37)OH,
Ile8-Asp22-GLP-1(7-36)NH2, Leu8-Lys22-GLP-1(7-37)OH, Leu8 Lys22-GLP-1(7-36)NH2, Ile8-Lys22-GLP-1(7-37)OH, Ile8-Lys22-GLP1(7-36)NH2, Ser8-Glu22-GLP-1(7-37)OH, Ser8-Glu22-GLP-1(736)NH2, Thr8-Glu22-GLP-1(7-37)OH, Thr8-Glu22-GLP-1(7-36)NH2,
Ser8-Asp22-GLP-1(7-37)OH, Ser8-Asp22-GLP-1(7-36)NH2, Thr8 Asp22-GLP-1(7-37)OH, Thr8-Asp22-GLP-1(7-36)NH2, Ser8-Lys22-GLP1(7-37)OH, Ser8-Lys22-GLP-1(7-36)NH2, Thr8-Lys22-GLP-1(737)OH, Thr8-Lys22-GLP-1(7-36)NH2, Glu22-GLP-1(7-37)OH, Glu22 GLP-1(7-36)NH2, Asp22-GLP-1(7-37)OH, Asp22-GLP-1(7-36)NH2,
Lys22-GLP-1(7-37)OH, Lys22-GLP-1(7-36)NH2,
33. The GLP-1 compound of Claim 32 wherein
Xaa7 is L-histidine;
Xaa8 is Gly or Val;
Xaa16 is Phe, Trp, Tyr, Ile, or Leu;
Xaa18 is Ser;
Xaa22 is Gly or Glu; and
Xaa25 is Ala;
Xaa33 is Val; and
Xaa37 is Gly, NH2, or is absent.
34. The GLP-1 compound of any one of Claims 32 or 33 wherein
Xaa22 is Glu.
35. The GLP-1 compound of any one of Claims 32, 33, or 34 wherein Xaa8 is Val.
36. The GLP-1 compound of Claim 35 wherein Xaa16 is Trp.
37. The GLP-1 compound of Claim 35 wherein Xaa16 is Phe.
38. The GLP-1 compound of Claim 35 wherein Xaa16 is Tyr.
39. The GLP-1 compound of Claim 32 wherein
Xaa7 is L-histidine;
Xaa8 is Gly or Val;
Xaa16 is Val;
Xaa18 is Trp, Tyr, Phe, Lys, Leu, Ile, or Val;
Xaa22 is Gly or Glu;
Xaa25 is Ala;
Xaa33 is Val; and
Xaa37 is Gly, NH2, or is absent.
40. The GLP-1 compound of any one of Claim 39 wherein
Xaa22 is Glu.
41. The GLP-1 compound of any one of Claims 39 or 40 wherein Xaa8 is Val.
42. The GLP-1 compound of Claim 41 wherein Xaa18 is Phe.
43. The GLP-1 compound of Claim 41 wherein Xaa18 is Tyr.
44. The GLP-1 compound of Claim 41 wherein Xaa18 is Trp.
45. The GLP-1 compound of Claim 41 wherein Xaa18 is Lys.
46. The GLP-1 compound of Claim 41 wherein Xaa18 is Ile.
47. The GLP-1 compound of Claim 41 wherein Xaa18 is Leu.
48. The GLP-1 compound of Claim 41 wherein Xaa18 is Val.
49. The GLP-1 compound of Claim 32 wherein
Xaa7 is L-histidine;
Xaa8 is Gly or Val;
Xaa16 is Val;
Xaa18 is Ser;
Xaa22 is Gly or Glu;
Xaa25 is Val, Ile, or Leu;
Xaa33 is Val; and
Xaa37 is Gly, NH2, or is absent.
50. The GLP-1 compound of Claims 49 wherein Xaa22 is
Glu.
51. The GLP-1 compound of Claims 50 wherein Xaa8 is
Val.
52. The GLP-1 compound of Claim 51 wherein Xaa25 is Val.
53. The GLP-1 compound of Claim 51 wherein Xaa25 is Ile.
54. The GLP-1 compound of Claim 51 wherein Xaa25 is Leu.
55. The GLP-1 compound of Claim 32 wherein
Xaa7 is L-histidine;
Xaa8 is Gly or Val;
Xaa16 is Val;
Xaa18 is Ser;
Xaa22 is Gly or Glu;
Xaa25 is Ala;
Xaa33 is Ile; and
Xaa37 is Gly, NH2, or is absent.
56. The GLP-1 compound of Claim 55 wherein Xaa22 is Glu.
57. The GLP-1 compound of claim 56 wherein Xaa8 is Val.
58. The GLP-1 compound of Claim 1 which is Val8-Trp19-Glu22 GLP-1 (7-37) OH.
59. The GLP-1 compound of Claim 1 which is Val8-Glu22-Val25
GLP-1 (7-37) OH.
60. The GLP-1 compound of Claim 1 which is Val8-Glu22-Ile33 GLP-1 (7-37) OH.
61. The GLP-1 compound of Claim 1 which is Val8-Trp16-Glu22Val25-Ile33-GLP-1 (7-37) OH.
62. The GLP-1 compound of Claim 1 which is Val8-Trp16-Glu22 Ile33-GLP-1 (7-37) OH.
63. The GLP-1 compound of Claim 1 which is Val8-Glu22-Val25 Ile33-GLP-1 (7-37) OH.
64. The GLP-1 compound of Claim 1 which is Val8-Trp16-Glu22 Val25-GLP-1(7-37)OH.
65. 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 1-64.
66. The method of Claim 65 wherein the subject is being treated for non-insulin dependent diabetes.
67. The method of Claim 65 wherein the subject is being treated prophylactically for non-insulin dependent diabetes.
68. The method of Claim 65 wherein the subject is being treated for obesity, stroke, myocardial infarction, stroke or irritable bowel syndrome.
69. The use of a GLP-1 compound of any one of Claims 1-64 in the manufacture of a medicament for the treatment of non-insulin dependent diabetes, obesity, stroke, myocardial infarction, or irritable bowel syndrome.
70. The use of Claim 69 wherein the medicament is used to treat non-insulin dependent diabetes.
71. The use of claim 70 wherein the medicament is used to treat obesity.