IP Library › Granted Patent US 7,538,185
Granted Patent B2
US 7,538,185 · App. 11/031,851 · Granted May 26, 2009

Glucagon-like peptide-1 analogs with long duration of action

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Quick Facts
Patent No.
US 7,538,185
App. No.
11/031,851
Granted
May 26, 2009
Kind
B2
Abstract

Novel GLP-1 analogs having improved biological potency as well as extended pharmacological activity are described herein. More specifically, the present invention relates to GLP-1 analogs (28 or 29 aa long) comprising amino acid substitutions at one or more of the following positions: 8, 20, 27, 30 and 33.

Claims (40)

1. A GLP-1 analog comprising the following sequence:

R1-His-X8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-X20-Glu-Gly-Gln-Ala-Ala-Lys-X27-Phe-Ile-X30-Trp-Leu-X33 (SEQ ID NOs: 1 to 11, depending on the nature of X33)

wherein:

(i) R1 is 2-hydroxybenzoyl or hydrogen; X8 is Ala or Gly; X20 is selected from the group consisting of Leu and Gly having a C 6 -C 20 alkyl side chain; X27 is Ala or Leu; X30 is Glu or Gln, and X33 is Val-Lys-Asn-NH 2 ; or

(ii) R1 is 2-hydroxybenzoyl or hydrogen; X8 is Ala or Gly; X20 is selected from the group consisting of Leu and Gly having a C 6 -C 20 alkyl side chain; X27 is Ala or Leu; X30 is Glu; and X33 is Lys-Asn-NH 2 ; or

(iii) R1 is 2-hydroxybenzoyl, trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X20 is selected from the group consisting of Leu and Gly having a C 6 C 20 alkyl side chain; X27 is Leu; X30 is Glu; and X33 is Lys-Asn-Aib-NH 2 ; or

(iv) R1 is trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X20 is selected from the group consisting of Leu and Gly having a C 6 -C 20 alkyl side chain; X27 is Ala or Leu; X30 is Glu; and X33 is Lys-Asn-NH 2 ; or

(v) R1 is trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X20 is (S)-Octylglycine; X27 is Ala or Leu; X30 is Glu, Gln or Asp; and X33 is Lys-Asn-NH 2 or Val-Lys-Asn-NH 2 ; or

(vi) the GLP-1 analog has a sequence selected from the group consisting of: SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO: 20; SEQ ID NO: 21; SEQ ID NO: 22; SEQ ID NO: 23; SEQ ID NO:24; SEQ ID NO: 25; SEQ ID NO:26, SEQ ID NO: 27, SEQ ID NO:28, SEQ ID NO: 29; SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32; SEQ ID NO: 33; SEQ ID NO: 34; SEQ ID NO: 35, SEQ ID NO:36, AND SEQ ID NO: 38.

2. The GLP-1 analog of claim 1 , wherein R1 is 2-hydroxybenzoyl or hydrogen; X8 is Ala or Gly; X27 is Ala or Leu; X30 is Glu or Gln, and X33 is Val-Lys-Asn-NH 2 .

3. The GLP-1 analog of claim 1 , wherein R1 is 2-hydroxybenzoyl or hydrogen; X8 is Ala or Gly; X27 is Ala or Leu; X30 is Glu; and X33 is Lys-Asn-NH 2 .

4. The GLP-1 analog of claim 1 , wherein R1 is 2-hydroxybenzoyl, trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X27 is Leu; X30 is Glu; and X33 is Lys-Asn-Aib-NH 2 .

5. The GLP-1 analog of claim 1 , wherein R1 is trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X27 is Ala or Leu; X30 is Glu; and X33 is Lys-Asn-NH 2 .

6. The GLP-1 analog of claim 1 , wherein R1 is trans-3-hexenoyl or hydrogen; X8 is Ala or Gly; X20 is (S)-Octylglycine; X27 is Ala or Leu; X30 is Glu, Gln or Asp; and X33 is Lys-Asn-NH 2 or Val-Lys-Asn-NH 2 .

7. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 16).

8. The GLP-1 analog of claim 1 , having the following sequence: 2-Hydroxybenzoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 17).

9. The GLP-1 analog of claim 1 , having the following sequence: 2-Hydroxybenzoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Aib-NH 2 (SEQ ID NO: 18).

10. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 19).

11. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 20).

12. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 21).

13. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH2 (SEQ ID NO: 22).

14. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 23).

15. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 24).

16. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 25).

17. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Ala-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 26).

18. The GLP-1 analog of claim 1 , having the following sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ ID NO: 27).

19. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ ID NO: 28).

20. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ ID NO: 29).

21. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Aib-Arg-NH 2 (SEQ ID NO: 30).

22. The GLP-1 analog of claim 1 , having the following sequence: 2-Hydroxybenzoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-NH 2 (SEQ ID NO: 31).

23. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 32).

24. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 33).

25. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 34).

26. The GLP-1 analog of claim 1 , having the following sequence: trans-3-hexenoyl-NH-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Val-Lys-Asn-NH 2 (SEQ ID NO: 35).

27. The GLP-1 analog of claim 1 , having the following sequence: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(S)-Octylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-NH 2 (SEQ ID NO: 36).

28. The GLP-1 analog of claim 1 , having the following sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-[(R)-Octadecylglycine]-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH 2 (SEQ ID NO: 38).

29. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients in combination with a GLP-1 analog according to claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to reduce serum glucose levels in a diabetic subject.

30. The pharmaceutical composition of claim 29 , comprising from about 1 mcg to about 10 mg of the GLP-1 analog or pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients in combination with a GLP-1 analog according to claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to promote production of cAMP from pancreatic beta cells.

32. The pharmaceutical composition of claim 31 , comprising from about 1 mcg to about 10 mg of the GLP-1 analog or pharmaceutically acceptable salt thereof.

Assignments (4)
TERMINATION OF SECURITY INTEREST Recorded Oct 14, 2008
From: BIOLEX THERAPEUTICS, INC.
To: OCTOPLUS SCIENCES B.V.; CHIENNA B.V.; OCTOPLUS DEVELOPMENT B.V.; OCTOPLUS TECHNOLOGIES B.V.
Reel/Frame 021701/0168 →
SECURITY AGREEMENT Recorded Jul 15, 2008
From: OCTOPLUS SCIENCES B.V.; CHIENNA B.V.; OCTOPLUS DEVELOPMENT B.V.; OCTOPLUS TECHNOLOGIES B.V.
To: BIOLEX THERAPEUTICS, INC.
Reel/Frame 021230/0881 →
SECURITY AGREEMENT Recorded May 30, 2008
From: OCTOPLUS SCIENCES B.V.; CHIENNA B.V.; OCTOPLUS DEVELOPMENT B.V.; OCTOPLUS TECHNOLOGIES B.V.
To: LSP III OMNI INVESTMENT COOPERATIEF U.A.; S.R. ONE, LIMITED
Reel/Frame 021018/0559 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 19, 2005
From: PERI, KRISHNA; ABRAN, DANIEL; HABI, ABDELKRIM
To: THERATECHNOLOGIES INC.
Reel/Frame 016993/0489 →