Claims
- 1. A GLP-1 derivative of formula I (SEQ ID NO:2): 7 8 9 10 11 12 13 14 15 16 17His-Xaa-Xaa-Gly-Xaa-Phe-Thr-Xaa-Asp-Xaa-Xaa- 18 19 20 21 22 23 24 25 26 27 28Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Phe- 29 30 31 32 33 34 35 36 37Ile-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-XaawhereinXaa at position 8 is Ala, Xaa at position 9 is Glu, Xaa at position 11 is Thr, Xaa at position 14 is Ser, Xaa at position 16 is Val, Xaa at position 17 is Ser, Xaa at position 18 is Ser, Xaa at position 19 is Tyr, Xaa at position 20 is Leu, Xaa at position 21 is Glu, Xaa at position 22 is Gly, Xaa at position 23 is Gln, Xaa at position 24 is Ala, Xaa at position 25 is Ala, Xaa at position 26 is Lys, Xaa at position 27 is Glu, Xaa at position 30 is Ala, Xaa at position 31 is Trp, Xaa at position 32 is Leu, Xaa at position 33 is Val, Xaa at position 34 is Arg, Xaa at position 35 is Gly, Xaa at position 36 is Arg, and Xaa at position 37 is Gly, wherein(a) the ε-amino group of Lys at position 26 is substituted with a lipophilic substituent, optionally via a spacer, (b) the lipophilic substituent is (i) CH3(CH2)nCO— wherein n is 6, 8, 10, 12, 14, 16, 18, 20 or 22, (ii) HOOC(CH2)mCO— wherein m is 10, 12, 14, 16, 18, 20 or 22, or (iii) lithochoyl, and (c) the spacer is (i) an unbranched alkane α,ω-dicarboxylic acid group having from 1 to 7 methylene groups, (ii) an amino acid residue except Cys, or (iii) γ-aminobutanoyl.
- 2. The GLP-1 derivative of claim 1, wherein the lipophilic substituent is linked to the ε-amino group of Lys via a spacer.
- 3. The GLP-1 derivative of claim 2, wherein the spacer is γ-glutamyl.
- 4. The GLP-1 derivative of claim 2, wherein the spacer is β-asparagyl.
- 5. The GLP-1 derivative of claim 2, wherein the spacer is glycyl.
- 6. The GLP-1 derivative of claim 2, wherein the γ-aminobutanoyl.
- 7. The GLP-1 derivative of claim 2, wherein the β-alanyl.
- 8. The GLP-1 derivative of claim 1, which is Lys26(Nε-tetradecanoyl), Arg34-GLP-1(7-37).
- 9. The GLP-1 derivative of claim 1, which is Lys26(Nε-(ω-carboxynonadecanoyl)), Arg34-GLP-1(7-37).
- 10. The GLP-1 derivative of claim 1, which is Lys26(Nε-(ω-carboxyheptadecanoyl)), Arg34-GLP-1(7-37).
- 11. The GLP-1 derivative of claim 1, which is Lys26(Nε-(ω-carboxyundecanoyl)), Arg34-GLP-1(7-37).
- 12. The GLP-1 derivative of claim 1, which is Lys26(Nε-(ω-carboxypentadecanoyl)), Arg34-GLP-1(7-37).
- 13. The GLP-1 derivative of claim 1, which is Lys26(Nε-lithochoyl),Arg34-GLP-1(7-37).
- 14. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γ-glutamyl(Nα-hexadecanoyl))), Arg34-GLP-1(7-37).
- 15. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γglutamyl(Nαtetradecanoyl))), Arg34-GLP-1(7-37).
- 16. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γglutamyl(Nαlithochoyl))), Arg34-GLP-1(7-37).
- 17. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γglutamyl(Nαoctadecanoyl))), Arg34-GLP-1(7-37).
- 18. The GLP-1 derivative of claim 1, which is Lys26(Nε-decanoyl), Arg34-GLP-1(7-37).
- 19. The GLP-1 derivative of claim 1, which is Lys26(Nε-hexadecanoyl), Arg34-GLP-1(7-37).
- 20. The GLP-1 derivative of claim 1, which is Lys26(Nε-octanoyl), Arg34-GLP-1(7-37).
- 21. The GLP-1 derivative of claim 1, which is Lys26(Nε-dodecanoyl), Arg34-GLP-1(7-37).
- 22. The GLP-1 derivative of claim 1, which is Lys26(Nε(N68 (γaminobutyroyl-(Nγ-hexadecanoyl))), Arg34-GLP-1(7-37).
- 23. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γ-D-glutamyl(Nαhexadecanoyl))), Arg34-GLP-1(7-37).
- 24. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γglutamyl(Nα-dodecanoyl))), Arg34-GLP-1(7-37).
- 25. The GLP-1 derivative of claim 1, which is Lys26(Nε-(βalanyl(Nα-hexadecanoyl))), Arg34-GLP-1(7-37).
- 26. The GLP-1 derivative of claim 1, which is Lys26(Nε-(α-glutamyl(Nα-hexadecanoyl))), Arg34-GLP-1(7-37).
- 27. The GLP-1 derivative of claim 1, which is Lys26(Nε-(γ-glutamyl(Nα-decanoyl))), Arg34-GLP-1(7-37).
- 28. A pharmaceutical composition comprising a GLP-1 derivative of claim 1 and a pharmaceutically acceptable vehicle or carrier.
- 29. A pharmaceutical composition of claim 28, further comprising an isotonic agent, a preservative and a buffer.
- 30. A pharmaceutical composition of claim 29, wherein the isotonic agent is sodium chloride, mannitol and glycerol.
- 31. A pharmaceutical composition of claim 29, wherein the preservative is phenol, m-cresol, methyl p-hydroxybenzoate or benzyl alcohol.
- 32. A pharmaceutical composition of claim 29, wherein the buffer is sodium acetate or sodium phosphate.
- 33. A pharmaceutical composition of claim 28, further comprising a surfactant.
- 34. A pharmaceutical composition of claim 28, further comprising zinc.
- 35. A pharmaceutical composition of claim 28, further comprising another antidiabetic agent.
- 36. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is human insulin.
- 37. A pharmaceutical composition of claim 35, wherein the antidiabetic agent is a hypoglycemic agent.
- 38. A pharmaceutical composition of claim 28, further comprising another antiobesity agent.
- 39. A method of treating diabetes, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.
- 40. A method of treating obesity, comprising administering to a patient a therapeutically effective amount of a GLP-1 derivative of claim 1.
Priority Claims (10)
Number |
Date |
Country |
Kind |
0931/96 |
Aug 1996 |
DK |
|
1259/96 |
Nov 1996 |
DK |
|
1470/96 |
Dec 1996 |
DK |
|
0263/98 |
Feb 1998 |
DK |
|
0264/98 |
Feb 1998 |
DK |
|
0268/98 |
Feb 1998 |
DK |
|
0272/98 |
Feb 1998 |
DK |
|
0274/98 |
Feb 1998 |
DK |
|
0508/98 |
Apr 1998 |
DK |
|
0509/98 |
Apr 1998 |
DK |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of Ser. No. 09/038,432 filed Mar. 11, 1998, now abandoned which is a continuation-in-part of Ser. No. 08/918,810 filed Aug. 26, 1997 now abandoned and of PCT application serial no. PCT/DK97/00340 filed Aug. 22, 1997, and claims priority of U.S. provisional application Ser. Nos. 60/035,904, 60/036,226, 60/036,255, 60/082,478, 60/082,480, 60/082,802, and 60/084,357 filed Jan. 24, 1997, Jan. 25, 1997, Jan. 24, 1997, Apr. 21, 1998, Apr. 21, 1998, Apr. 23, 1998, and May 5, 1998, respectively, and of Danish application serial nos. 0931/96, 1259/96, 1470/96, 0263/98, 0264/98, 0268/98, 0272/98, 0274/98, 0508/98, and 0509/98 filed Aug. 30, 1996, Nov. 8, 1996, Dec. 20, 1996, Feb. 27, 1998, Feb. 27, 1998, Feb. 27, 1998, Feb. 27, 1998, Feb. 27, 1998, Apr. 8, 1998, and Apr. 8, 1998, respectively, the contents of each of which is fully incorporated herein by reference.
US Referenced Citations (4)
Foreign Referenced Citations (12)
Number |
Date |
Country |
0 708 179 |
Apr 1996 |
EP |
WO 9011296 |
Oct 1990 |
WO |
WO 9111457 |
Aug 1991 |
WO |
WO 9507931 |
Mar 1995 |
WO |
WO 9531214 |
Nov 1995 |
WO |
WO 9629344 |
Sep 1996 |
WO |
WO 9629342 |
Sep 1996 |
WO |
WO 8706941 |
Nov 1997 |
WO |
WO 9808871 |
Mar 1998 |
WO |
WO 9808531 |
Mar 1998 |
WO |
WO 9808873 |
Mar 1998 |
WO |
WO 9819698 |
May 1998 |
WO |
Non-Patent Literature Citations (2)
Entry |
Kim et al., (1994) J. of Pharma, Sciences 83(8);1175-1180. |
Clodfelter et al., (1998) Pharmaceutical Res. 15(2):254-262. |
Provisional Applications (7)
|
Number |
Date |
Country |
|
60/035904 |
Jan 1997 |
US |
|
60/036226 |
Jan 1997 |
US |
|
60/036255 |
Jan 1997 |
US |
|
60/082478 |
Apr 1998 |
US |
|
60/082480 |
Apr 1998 |
US |
|
60/082802 |
Apr 1998 |
US |
|
60/084357 |
May 1998 |
US |
Continuation in Parts (3)
|
Number |
Date |
Country |
Parent |
09/038432 |
Mar 1998 |
US |
Child |
09/258750 |
|
US |
Parent |
08/918810 |
Aug 1997 |
US |
Child |
09/038432 |
|
US |
Parent |
PCT/DK97/00340 |
Aug 1997 |
US |
Child |
08/918810 |
|
US |