Double-acylated GLP-1 derivatives
The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1(7-37), and a maximum of ten amino acid modifications as compared to GLP-1(7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which derivative comprises two albumin binding moieties attached to K 26 and K 37 , respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: Chem. 1, Chem. 2, Chem. 3 or Chem. 4; or a pharmaceutically acceptable salt, amide, or ester thereof.
1. A derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1(7-37), wherein the first K residue is designated K 37 , and the second K residue is designated K 26 , which analogue has a maximum of three amino acid modifications as compared to GLP-1(7-37), where two of the modifications are K 37 and a Q or an R at a position corresponding to position 34 of GLP-1(7-37);
which derivative comprises an albumin binding moiety attached to each of K 26 and K 37 respectively, wherein the albumin binding moiety comprises a protracting moiety of formula Chem. 2a:
HOOC—C 6 H 4 —O—(CH 2 ) y —CO—*,
in which y is an integer in the range of 7-15;
or a pharmaceutically acceptable salt, amide, or ester thereof.
2. The derivative of claim 1 , wherein the analogue has two amino acid modifications as compared to GLP-1(7-37).
3. The derivative of claim 1 , wherein the analogue comprises Imp 7 or Aib 8 .
4. The derivative of claim 3 , wherein the analogue comprises Aib 8 .
5. The derivative of claim 4 , wherein the analogue comprises the following amino acid modifications, as compared to GLP-1(7-37) (SEQ ID NO: 1): (8Aib, 34R, 37K).
6. The derivative of claim 5 , wherein the albumin binding moiety further comprises Chem. 6 and/or Chem. 5:
wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5.
7. The derivative of claim 1 , wherein the albumin binding moiety further comprises Chem. 6 and/or Chem. 5:
wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5.
8. The derivative of claim 7 , wherein y is 9.
9. A compound selected from the following:
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 12,
where the amino acid sequence is that of SEQ ID NO: 9,
where the amino acid sequence is that of SEQ ID NO: 10,
where the amino acid sequence is that of SEQ ID NO: 10,
where the amino acid sequence is that of SEQ ID NO: 8,
where the amino acid sequence is that of SEQ ID NO: 13,
where the amino acid sequence is that of SEQ ID NO: 7,
where the amino acid sequence is that of SEQ ID NO: 9,
where the amino acid sequence is that of SEQ ID NO: 9,
where the amino acid sequence is that of SEQ ID NO: 6,
where the amino acid sequence is that of SEQ ID NO: 9,
where the amino acid sequence is that of SEQ ID NO: 14,
where the amino acid sequence is that of SEQ ID NO: 7,
and Chem. 68:
where the amino acid sequence is that of SEQ ID NO: 6, or a pharmaceutically acceptable salt, amide, or ester of any of these compounds.
10. A method for treating type 2 diabetes in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a derivative according to claim 1 to a subject in need of such treatment.
11. A method for treating type 2 diabetes in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to claim 9 to a subject in need of such treatment.
12. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
13. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
14. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
15. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
16. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
17. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 12, or a pharmaceutically acceptable salt, amide, or ester of the compound.
18. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 9, or a pharmaceutically acceptable salt, amide, or ester of the compound.
19. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 10, or a pharmaceutically acceptable salt, amide, or ester of the compound.
20. A compound according to claim 1 which is
where the amino acid sequence is that of SEQ ID NO: 10, or a pharmaceutically acceptable salt, amide, or ester of the compound.
21. A compound according to claim 1 which is
where the amino acid sequence is that of SEQ ID NO: 8, or a pharmaceutically acceptable salt, amide, or ester of the compound.
22. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 13, or a pharmaceutically acceptable salt, amide, or ester of the compound.
23. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
24. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 9, or a pharmaceutically acceptable salt, amide, or ester of the compound.
25. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 9, or a pharmaceutically acceptable salt, amide, or ester of the compound.
26. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 6, or a pharmaceutically acceptable salt, amide, or ester of the compound.
27. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 9, or a pharmaceutically acceptable salt, amide, or ester of the compound.
28. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 14, or a pharmaceutically acceptable salt, amide, or ester of the compound.
29. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 7, or a pharmaceutically acceptable salt, amide, or ester of the compound.
30. A compound according to claim 9 which is
where the amino acid sequence is that of SEQ ID NO: 6, or a pharmaceutically acceptable salt, amide, or ester of the compound.