Double-acylated GLP-1 derivatives
The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position T of GLP-1(7-37), where T is an integer in the range of 7-37 except 18 and 27; and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K 27 , and the second K residue is designated K T ; which derivative comprises two albumin binding moieties attached to K 27 and K T , respectively, via a linker, wherein the albumin binding moiety comprises a protracting moiety selected from HOOC—(CH 2 ) x —CO— and HOOC—C 6 H 4 —O—(CH 2 ) y —CO—; in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; wherein the linker comprises an element of the formula —NH—(CH 2 ) 2 —(O—(CH 2 ) 2 ) k —O—(CH 2 ) n —CO—, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel GLP-1 analogs. The derivatives are suitable for oral administration.
1. A derivative of a GLP-1 analogue,
which analogue comprises a first K residue at a position corresponding to position 27 of GLP-1(7-37) (SEQ ID NO: 1); a second K residue at a position corresponding to position 36 of GLP-1(7-37), and a maximum of ten amino acid changes as compared to GLP-1(7-37); wherein the first K residue is designated K27, and the second K residue is designated K36;
which derivative comprises two protracting moieties attached to K27 and K36, respectively, via a linker, wherein
the protracting moiety is selected from the group consisting of Chem. 2 and Chem. 1:
HOOC—C 6 H4 4 —O—(CH 2 )y—CO—* Chem. 2
HOOC(CH 2 )x—CO—*, Chem. 1
in which x is an integer in the range of 6-16, and y is an integer in the range of 3-17; and
the linker comprises Chem. 5:
wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5 and wherein Chem. 5 is included m times, wherein m is an integer in the range of 1-10;
or a pharmaceutically acceptable salt, amide, or ester thereof.
2. The derivative of claim 1 , wherein the linker further comprises a Glu di-radical selected from the group consisting of
wherein the Glu di-radical is included p times, wherein p is an integer in the range of 1-2.
3. The derivative of claim 2 , wherein the analogue comprises no K residues other than the first and the second K residue.
4. The derivative of claim 3 , wherein the protracting moiety is Chem. 1.
5. The derivative of claim 4 , wherein x is an integer in the range of 12-16.
6. The derivative of claim 3 , wherein the protracting moiety is Chem. 2.
7. The derivative of claim 6 , wherein k is 1.
8. The derivative of claim 7 , wherein n is 1.
9. The derivative of claim 8 , wherein m is an integer in the range of 1-3.
10. The derivative of claim 9 , wherein y is an integer in the range of 9-11.
11. The derivative of claim 10 , wherein the linker further comprises a Glu di-radical that is Chem. 6.
12. The derivative of claim 11 , wherein m is 2.
13. The derivative of claim 12 , wherein y is 9.
14. The derivative of claim 13 , wherein p is 1.
15. The derivative of claim 1 , wherein the derivative is a derivative of a GLP-1 analogue of Formula I (SEQ. ID NO: 3):
Xaa7-Xaa8-Glu-Gly-Thr-Xaa12-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26-Lys-Phe-Ile-Xaa30-Xaa31-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39,
wherein
Xaa7 is selected from the group consisting of L-histidine, imidazopropionyl, α-hydroxy-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, N α -formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, and 4-pyridylalanine;
Xaa8 is selected from the group consisting of Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, and (1-aminocyclooctyl) carboxylic acid;
Xaa12 is selected from the group consisting of Lys and Phe;
Xaa16 is selected from the group consisting of Val and Leu;
Xaa18 is selected from the group consisting of Ser, Arg, Asn, Gln, and Glu;
Xaa19 is selected from the group consisting of Tyr and Gln;
Xaa20 is selected from the group consisting of Leu, Lys, and Met;
Xaa22 is selected from the group consisting of Gly, Glu, Lys, and Aib;
Xaa23 is selected from the group consisting of Gln, Glu, and Arg;
Xaa24 is selected from the group consisting of Ala and Lys;
Xaa25 is selected from the group consisting of Ala and Val;
Xaa26 is selected from the group consisting of Val, His, and Arg;
Xaa30 is selected from the group consisting of Ala, Glu, and Arg;
Xaa31 is selected from the group consisting of Trp and His;
Xaa34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa35 is selected from the group consisting of Gly, Aib and absent;
Xaa36 is Lys;
Xaa37 is selected from the group consisting of Gly, Ala, Glu, Pro, Lys, Arg, and absent;
Xaa38 is selected from the group consisting of Ser, Gly, Ala, Glu, Gln, Pro, Arg, and absent; and
Xaa39 is selected from the group consisting of Gly and absent.
16. The derivative of claim 15 , wherein the linker further comprises a Glu di-radical selected from the group consisting of
wherein the Glu di-radical is included p times, wherein p is an integer in the range of 1-2.
17. The derivative of claim 16 , wherein the analogue comprises no K residues other than the first and the second K residue.
18. The derivative of claim 17 , wherein
Xaa7 is L-histidine;
Xaa8 is selected from the group consisting of Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, and (1-aminocyclooctyl) carboxylic acid;
Xaa12 is Phe;
Xaa16 is Val;
Xaa18 is Ser;
Xaa19 is Tyr;
Xaa20 is selected from the group consisting of Leu; and Met;
Xaa22 is selected from the group consisting of Gly, Glu, and Aib;
Xaa23 is selected from the group consisting of Gln, Glu, and Arg;
Xaa24 is Ala;
Xaa25 is selected from the group consisting of Ala and Val;
Xaa26 is selected from the group consisting of Val, His, and Arg;
Xaa30 is selected from the group consisting of Ala, Glu and Arg;
Xaa31 is selected from the group consisting of Trp and His;
Xaa34 is selected from the group consisting of Glu, Asn, Gly, Gln, and Arg;
Xaa35 is Gly; and
Xaa37 is selected from the group consisting of Gly, Ala, Glu, Pro, Arg, and absent.
19. The derivative of claim 18 , wherein
Xaa20 is Leu;
Xaa23 is Gln; and
Xaa37 is selected from the group consisting of Gly or absent.
20. The derivative of claim 16 , wherein
Xaa26 is selected from the group consisting of His and Arg; and
Xaa34 is selected from the group consisting of Gly, Gln, and Arg.
21. The derivative of claim 20 , wherein
Xaa22 is Glu.
22. The derivative of claim 21 , wherein
Xaa30 is Glu; and
Xaa34 is Arg.
23. The derivative of claim 22 , wherein
Xaa8 is Aib; and
Xaa26 is Arg.
24. The derivative of claim 23 , wherein
Xaa38 is Glu; and
Xaa39 is Gly.
25. The derivative of claim 24 , wherein the protracting moiety is Chem. 2.
26. The derivative of claim 25 , wherein the Glu di-radical is Chem. 6.
27. The derivative of claim 26 , wherein n is 1 and k is 1.
28. The derivative of claim 27 , wherein m is an integer in the range of 1-3.
29. The derivative of claim 27 , wherein y is an integer in the range of 9-11.
30. The derivative of claim 29 , wherein p is 1.
31. The derivative of claim 29 , wherein the protracting moiety is Chem. 2.
32. The derivative of claim 31 , wherein the Glu di-radical is Chem. 6.
33. The derivative of claim 32 , wherein n is 1 and k is 1.
34. The derivative of claim 33 , wherein m is an integer in the range of 1-3.
35. The derivative of claim 34 , wherein y is an integer in the range of 9-11.
36. The derivative of claim 35 , wherein p is 1.
37. A derivative according to claim 1 , selected from the following:
where the amino acid sequence is that of SEQ ID No. 5,
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. 13,
where the amino acid sequence is that of SEQ ID No. 15,
where the amino acid sequence is that of SEQ ID No. 16,
where the amino acid sequence is that of SEQ ID No. 24,
where the amino acid sequence is that of SEQ ID No. 26,
where the amino acid sequence is that of SEQ ID No. 29,
where the amino acid sequence is that of SEQ ID No. 34,
where the amino acid sequence is that of SEQ ID No. 35; or a pharmaceutically acceptable salt, amide, or ester of any of the preceding derivatives.
38. A derivative according to claim 37 which is Chem. 80
where the amino acid sequence is that of SEQ ID No. 34, or a pharmaceutically acceptable salt, amide, or ester of the preceding derivative.
39. A pharmaceutical composition comprising a derivative according to claim 1 and a pharmaceutically acceptable excipient.
40. A method for treating diabetes in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 39 .
41. A method for treating eating disorders in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 39 .
42. A pharmaceutical composition comprising a derivative according to claim 15 and a pharmaceutically acceptable excipient.
43. A method for treating diabetes in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 42 .
44. A method for treating eating disorders in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 42 .
45. A pharmaceutical composition comprising a derivative according to claim 37 and a pharmaceutically acceptable excipient.
46. A method for treating diabetes in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 45 .
47. A method for treating eating disorders in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 45 .
48. A pharmaceutical composition comprising a derivative according to claim 38 and a pharmaceutically acceptable excipient.
49. A method for treating diabetes in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 48 .
50. A method for treating eating disorders in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 48 .