Derivatives of GLP-1 analogs
The present invention relates to a pharmaceutical composition comprising a GLP-1 derivative having a lipophilic substituent; and a surfactant.
1. A glucagon-like peptide 1(GLP-1) derivative of formula I:
7 8 9 10 11 12 13 14 15 16 17
Xaa-Xaa-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-
18 19 20 21 22 23 24 25 26 27 28
Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe-
29 30 31 32 33 34 35 36 37 38 39
Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa
wherein
Xaa at position 7 is His, a modified amino acid, or is deleted
Xaa at position 8 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, or Asp,
Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, or Lys,
Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 21 is Glu, Asp, or Lys,
Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, or Lys,
Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys,
Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 26 is Lys, Arg, Gln, Glu, Asp, or His,
Xaa at position 27 is Glu, Asp, or Lys,
Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys,
Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys,
Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys,
Xaa at position 34 is Lys, Arg, Glu, Asp, or His,
Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,
Xaa at position 36 is Arg, Lys, Glu, Asp, or His,
Xaa at position 37 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys or is deleted
Xaa at position 38 is Arg, Lys, Glu, Asp, or His, or is deleted,
Xaa at position 39 is Arg or is deleted,
or
(a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that
(i) when the amino acid at position 37 or 38 is deleted, then each amino acid downstream of the amino acid is also deleted,
(ii) the GLP-1 derivative contains only one Lys and the Lys is not the N-terminal or C-terminal amino acid of the derivative,
(iii) a lipophilic substituent of from 12 to 25 carbons is attached, optionally via a spacer, to the ε-amino group of the Lys, and
the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP- 1 does not exceed five.
2. The GLP-1 derivative of claim 1 , wherein
Xaa at position 7 is His,
Xaa at position 8 is Ala,
Xaa at position 26 is Arg, Gln, Glu, Asp, or His, and
the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 does not exceed three.
3. The GLP-1 derivative of claim 2 , wherein Xaa at position 34 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, and Xaa at position 39 is deleted.
4. The GLP-1 derivative of claim 3 , wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 does not exceed two.
5. The GLP-1 derivative of claim 2 , wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 is one.
6. The GLP-1 derivative of claim 2 , wherein Xaa at position 34 is Arg, Glu, Asp, or His.
7. The GLP-1 derivative of claim 6 , wherein Xaa at position 18 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7–36), (7–37) or (7–38).
8. The GLP-1 derivative of claim 6 , wherein Xaa at position 23 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7–36), (7–37) or (7–38).
9. The GLP-1 derivative of claim 6 , wherein Xaa at position 27 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1 (7–36), (7–37) or (7–38).
10. The GLP-1 derivative of claim 6 , wherein Xaa at position 36 is Lys, Xaa at position 37 is Gly, Xaa at position 38 is Arg or is deleted, Xaa at position 39 is deleted and each of the other Xaa is the amino acid in the native form of GLP-1(7–37) or (7–38).
11. The GLP-1 derivative of claim 6 , wherein Xaa at position 38 is Lys, Xaa at position 39 is Arg and each of the other Xaa is the amino acid in the native form of GLP-1(7–39).
12. The GLP-1 derivative of claim 1 , wherein Xaa at position 26 is Arg, Gln, Glu, Asp, or His.
13. The GLP-1 derivative of claim 12 , wherein Xaa at position 34 is Arg, Glu, Asp, or His.
14. The GLP-1 derivative of claim 13 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Ala.
15. The GLP-1 derivative of claim 13 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Thr, Ser, Gly or Val.
16. The GLP-1 derivative of claim 13 , wherein the Xaa at position 7 is deleted.
17. The GLP-1 derivative of claim 16 , wherein the Xaa at position 8 is Ala.
18. The GLP-1 derivative of claim 16 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
19. The GLP-1 derivative of claim 13 , wherein the Xaa at position 7 is a modified amino acid.
20. The GLP-1 derivative of claim 19 , wherein the Xaa at position 8 is Ala.
21. The GLP-1 derivative of claim 19 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
22. The GLP-1 derivative of claim 13 , wherein Xaa at position 18, 23 or 27 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, and Xaa at position 39 is deleted.
23. The GLP-1 derivative of claim 22 , wherein Xaa at position 36 is Lys, Xaa at position 37 is Gly, Xaa at position 38 is Arg, and Xaa at position 39 is deleted.
24. The GLP-1 derivative of claim 22 , wherein Xaa at position 38 is Lys, Xaa at position 37 is Gly, and Xaa at position 39 is Arg.
25. The GLP-1 derivative of claim 12 , wherein Xaa at position 34 is Lys, Xaa at position 37 is Gly or is deleted, Xaa at position 38 is Arg or is deleted, and Xaa at position 39 is deleted.
26. The GLP-1 derivative of claim 25 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Ala.
27. The GLP-1 derivative of claim 25 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Thr, Ser, Gly or Val.
28. The GLP-1 derivative of claim 25 , wherein the Xaa at position 7 is deleted.
29. The GLP-1 derivative of claim 28 , wherein the Xaa at position 8 is Ala.
30. The GLP-1 derivative of claim 28 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
31. The GLP-1 derivative of claim 25 , wherein the Xaa at position 7 is a modified amino acid.
32. The GLP-1 derivative of claim 31 , wherein the Xaa at position 8 is Ala.
33. The GLP-1 derivative of claim 31 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
34. The GLP-1 derivative of claim 1 , wherein
Xaa at position 26 is Lys and
Xaa at position 34 is Arg, Glu, Asp, or His, and
the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1(7–36), (7–37) or (7–38) does not exceed three.
35. The GLP-1 derivative of claim 34 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Ala.
36. The GLP-1 derivative of claim 34 , wherein
Xaa at position 7 is His, and
Xaa at position 8 is Thr, Ser, Gly or Val.
37. The GLP-1 derivative of claim 34 , wherein Xaa at position 7 is a modified amino acid.
38. The GLP-1 derivative of claim 37 , wherein the Xaa at position 8 is Ala.
39. The GLP-1 derivative of claim 37 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
40. The GLP-1 derivative of claim 34 , wherein Xaa at position 7 is deleted.
41. The GLP-1 derivative of claim 40 , wherein the Xaa at position 8 is Ala.
42. The GLP-1 derivative of claim 40 , wherein the Xaa at position 8 is Thr, Ser, Gly or Val.
43. A pharmaceutical composition comprising:
a) a GLP-1 derivative according to claim 1 , and
b) a buffer,
wherein the pH of the composition is between 7.4 and 8.0.
44. The pharmaceutical composition of claim 43 , further comprising a preservative and an isotonicity agent.
45. A pharmaceutical composition comprising:
c) a GLP-1 derivative according to claim 34 , and
d) a buffer,
wherein the pH of the composition is between 7.4 and 8.0.
46. The pharmaceutical composition of claim 45 , further comprising a preservative and an isotonicity agent.
47. A pharmaceutical composition comprising:
e) a GLP-1 derivative according to claim 35 , and
f) a buffer,
wherein the pH of the composition is between 7.4 and 8.0.
48. The pharmaceutical composition of claim 47 , further comprising a preservative and an isotonicity agent.