Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2003018516 - 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

[ EN ]

CLAI S

What is claimed is:

1. A GLP-1 compound comprising the amino acid sequence of formula 1 (SEQ ID NO:l)
Xaa -Xaa8-Glu-Gly-Thr-Xaaι2-Thr-Ser-Asp-Xaai6-Ser- Xaa18-Xaai9-Xaa20-Glu-Xaa22-Gln-Ala-Xaa25-Lys-Xaa27- Phe-Ile-Xaa3cι-Trp-Leu-Xaa33-Lys-Gly-Arg-Xaa37
Formula 1 (SEQ ID NO: 1)

wherein:
Xaa7 is: L-histidine, D-histidine, desamino-histidine, 2- amino-histidine, β-hydroxy-histidine,
homohistidine, α-fluoromethyl-histidine, or α- methyl-histidine ;
Xaa8 is: Ala, Gly, Val, Leu, He, Ser, or Thr;
Xaai2 is: Phe, Trp, or Tyr;
Xaai6 is: Val, Trp, He, Leu, Phe, or Tyr;
Xaaie is: Ser, Trp, Tyr, Phe, Lys, He, Leu, or Val ;
Xaai9 is: Tyr, Trp, or Phe;
Xaa2o is: Leu, Phe, Tyr, or Trp;
Xaa22 is: Gly, Glu, Asp, Lys ;
Xaa25 is: Ala, Val, He, or Leu;
Xaa27 is: Glu, He, or Ala;
Xaa30 is: Ala or Glu
Xaa33 is: Val, or He; 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-GLP- l(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, He8-GLP-1 (7-37)OH, He8-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- Tyr -12 - GLP-1 ( 7 - 36 ) NH2 Val8 -Tyr16 -GLP-1 (7-37) OH, Val8-Tyr16- GLP-1 (7-36)NH2 Val8-Glu22-GLP-l(7-37)OH, Val8-Glu22- GLP-1 (7-36)NH2 Gly8-Glu22-GLP-l(7-37)OH, Gly8-Glu22- GLP-1 (7-36)NH2 Val8-Asp22-GLP-l(7-37)OH, Val8- Asp -2"2 GLP-1 (7-36)NH2 Gly8-Asp22-GLP-1 (7-37) OH, Gly8- Asp 22 GLP-1 (7-36)NH2 Val8-Lys22-GLP-l(7-37)OH, Val8- Lys 22 GLP-1 (7-36)NH2 Gly8-Lys22-GLP-l(7-37)OH, Gly8- Lys 22 GLP-1 (7-36)NH2 Leu8-Glu22-GLP-1 (7-37) OH, Leu8- Glu 22 GLP-1 (7-36)NH2 Ile8-Glu22-GLP-1 (7-37) OH, Ile8- Glu22- GLP-1 (7-36)NH2 Leu8 -Asp22 -GLP-1 (7-37) OH, Leu8- Asp 22 GLP-1 (7-36)NH2 He8-Asp22-GLP-l(7-37)OH, Ile8-Asp 22 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-Glu22- GLP-1 (7-36)NH2 Thr8-Glu22-GLP-l(7-37)OH, Thr8-Glu22- GLP-1 (7-36)NH2 Ser8-Asp22-GLP-1 (7-37) OH, Ser8- Asp -22 GLP-1 (7-36)NH2 Thr8 -Asp22 -GLP-1 (7-37) OH, Thr8-Asp 22 GLP-1 (7-36)NH2 Ser8-Lys22-GLP-l(7-37)OH, Ser8-Lys 22 GLP-1 (7-36)NH2 Thr8 -Lys22 -GLP-1 (7-37) OH, Thr8-Lys 22 GLP-1 (7-36)NH2 Glu22-GLP-l(7-37)OH, Glu22-GLP-1 (7-36)NH2, Asp22-GLP-1 (7-37) OH, Asp22-GLP-1 (7-36) NH2, Lys22-GLP-l(7-37)OH, Lys2 -GLP-1 (7-36) NH2, Val8-Ala27-GLP-1 (7-37) OH, Val8-Glu2 -Ala27-GLP-1 (7-37) OH, Val8-Glu30-GLP-1(7-37) OH, Val8-Glu30-GLP-1 (7-36) NH2, Gly8-Glu30-GLP-1 (7-37) OH, Gly8-Glu30-GLP-1(7-36)NH2, Leu8-Glu30-GLP-1 (7-37) OH, Leu8-Glu30-GLP-1(7-36)NH2, He8-Glu30-GLP-1 (7-37) OH, He8-Glu30-GLP-1(7-36)NH2, Ser8-Glu30-GLP-1 (7-37) OH, Ser8-Glu30-GLP-1(7-36)NH2, Thr8-Glu30-GLP-1 (7-37) OH, Thr8-Glu30-GLP-1(7-36)NH2, Val8-His37-GLP-1 (7-37) OH, Val8-His37-GLP-1(7-36)NH2, Gly8-His37-GLP-1 (7-37) OH, Gly8-His37-GLP-1(7-36)NH2, Leu8-His37-GLP-1 (7-37) OH, Leu8-His37-GLP-1(7-36)NH2, He8-His37-GLP-1 (7- 37) OH, He8-His37-GLP-1(7-36)NH2, Ser8-His37-GLP-1 (7- 37) OH, Ser8-His37-GLP-1 (7-36) NH2, Thr8-His37-GLP-1 (7- 37) 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 (7- 36)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.

The GLP-1 compound of Claim 5 wherein Xaa22 is Glu.

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
Xaa2 is Glu and Xaa37 is His.

10. 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 and XaaX6 is Tyr, Trp, Leu, or He.

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, Xaaχ6 is Tyr, Trp, Leu, or He, 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, Xaai6 is Tyr, Trp, Leu, or He, 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, He, 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, He, 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, He, or Val and Xaa37 is His.

18. The GLP-1 compound of any one of Claims 14, 15, 16, or
17 wherein Xaa25 is Val or He.

19. The GLP-1 compound of any one of Claims 1 through 4 wherein Xaa7 is L-histidine, Xaa8 is Val or Gly, Xaa22 i Glu, Asp, or Lys and Xaa33 is He.

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 He.

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 He, 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, He, Leu, or Val .

24. The GLP-1 compound of Claim 23 wherein Xaa2 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, Xaai8 is Trp, Tyr, Phe, Lys, He, 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, Xaaι8 is Trp, Tyr, Phe, Lys, He, Leu, or Val and Xaa37 is His.

27. The GLP-1 compound of any one of Claims 23, 24, 25, and 26 wherein XaaX8 is Trp, Tyr, or He.

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 Xaai9 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, Xaai9 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, Xaai9 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-Xaaι6-Ser- Xaaι8-Tyr-Leu-Glu-Xaa22-Gln-Ala-Xaa25-Lys-Glu-Phe- He-Ala-Trp-Leu-Xaa33-Lys-Gly-Arg-Xaa37
Formula II (SEQ ID NO: 2)
wherein:
Xaa is: L-histidine, D-histidine, desamino-histidine, 2- amino-histidine , β-hydroxy-histidine ,
homohistidine, α-fluoromethyl-histidine, or α- methyl -histidine;
Xaa8 is: Gly, Ala, Val, Leu, He, Ser, or Thr;
Xaaie is: Val, Phe, Tyr, or Trp;
Xaaie is: Ser, Tyr, Trp, Phe, Lys, He, Leu, or Val;
Xaa22 is: Gly, Glu, Asp, or Lys;
Xaa25 is: Ala, Val, He, or Leu;
Xaa33 is: Val or He; 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-l(7-37)OH, Leu8-GLP-1 (7-36) NH2, He8-GLP-1 (7-37) OH, He8-GLP-1(7-36)NH2, Ser8-GLP-1 (7-37) OH, Ser8-GLP-1 (7-36) NH2, Thr8-GLP-l(7-37)OH, Thr8-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, Gly8-Glu22-GLP-1 (7-36) NH2, Val8-Asp22-GLP-1 (7-37) OH, Val8-Asp22-GLP-1(7-36)NH2, Gly8-Asp22-GLP-l(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-l(7-37)OH, Gly8-Lys22-GLP-1 (7-36) NH2, Leu8- Glu22-GLP-1 (7-37) OH, Leu8-Glu22-GLP-1 (7-36) NH2 , He8-Glu22-GLP-l(7-37)OH, Ile8-Glu22-GLP-1(7-36)NH2, Leu8 -Asp22 -GLP-1 (7-37)OH, Leu8-Asp22-GLP-1 (7-36)NH2, He8-Asp22-GLP-1 (7-37) OH, He8-Asp22-GLP-1(7-36)NH2, Leu8-Lys22-GLP-1 (7-37) OH, Leu8-Lys22-GLP-1 (7-36)NH2, He8-Lys22-GLP-1 (7-37) OH, He8-Lys22-GLP-1(7-36)NH2, Ser8-Glu 2-GLP-l(7-37)OH, Ser8-Glu22-GLP-1 (7-36)NH2, Thr8-Glu22-GLP-1 (7-37) OH, Thr8-Glu22-GLP-1 (7-36) NH2, Ser8-Asp22-GLP-1 (7-37) OH, Ser8-Asp2 -GLP-1 (7-36) NH2, Thr8-Asp22-GLP-l(7-37)OH, Thr8 -Asp22 -GLP-1 (7-36) NH2, Ser8-Lys22-GLP-l(7-37)OH, Ser8-Lys22-GLP-1 (7-36)NH2, Thr8-Lys22-GLP-1 (7- 37)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-l(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, He, 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 Xaaι6 is Trp.

37. The GLP-1 compound of Claim 35 wherein Xaaι6 is Phe.

38. The GLP-1 compound of Claim 35 wherein Xaaie is Tyr.

39. The GLP-1 compound of Claim 32 wherein
Xaa7 is L-histidine;
Xaa8 is Gly or Val;
Xaaiε is Val ;
Xaai8 is Trp, Tyr, Phe, Lys, Leu, He, or Val;

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 Xaai8 is Tyr.

44. The GLP-1 compound of Claim 41 wherein Xaa18 is Trp.

45. The GLP-1 compound of Claim 41 wherein Xaaι8 is Lys.

46. The GLP-1 compound of Claim 41 wherein Xaaι8 is He.

47. The GLP-1 compound of Claim 41 wherein Xaaι8 is Leu.

48. The GLP-1 compound of Claim 41 wherein Xaai8 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;

Xaa25 is Val, He, 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 He.

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;
Xaaiε is Val;
Xaaα8 is Ser;

Xaa25 is Ala;
Xaa33 is He; and
Xaa3 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-l(7-37)OH.

59. The GLP-1 compound of Claim 1 which is Val8-Glu22-Val25 GLP-l(7-37)OH.

60. The GLP-1 compound of Claim 1 which is Val8-Glu 2-He33- GLP-l(7-37)OH.

61. The GLP-1 compound of Claim 1 which is Val8-Trp16-Glu22- Val25-Ile33-GLP-l(7-37)OH.

62. The GLP-1 compound of Claim 1 which is Val -Trp 16-G /-nl.u,22

He33-GLP-l(7-37)OH.

63. The GLP-1 compound of Claim 1 which is Val8-Glu22-Val25- He33-GLP-l(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.