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 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 analogues. 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 20 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 K 27 , and the second K residue is designated K 20 ;
which derivative comprises two protracting moieties attached to K 27 and K 20 , respectively, via a linker, wherein
the protracting moiety is selected from Chem. 2 and Chem. 1:
HOOC—C 6 H 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;
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:
3. The derivative of claim 1 , wherein the linker is attached to the epsilon-amino group of the K 27 and the K 20 .
4. The derivative of claim 1 , wherein the analogue comprises no K residues other than the first and the second K residue.
5. The derivative of claim 1 , wherein x is 12.
6. The derivative of claim 1 , wherein y is 9 or 11.
7. The derivative of claim 1 , wherein k is 1.
8. The derivative of claim 1 , wherein n is 1.
9. The derivative of claim 1 , wherein the analogue comprises a GLP-1 analogue of Formula I (SEQ ID NO:3):
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Xaa 24 -Xaa 25 -Xaa 26 -Lys-Phe-Ile-Xaa 30 -Xaa 31 -Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 ,
wherein
Xaa 7 is 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 or 4-pyridylalanine;
Xaa 8 is 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, or (1-aminocyclooctyl) carboxylic acid;
Xaa 12 is Lys or Phe;
Xaa 16 is Val or Leu;
Xaa 18 is Ser, Arg, Asn, Gln, or Glu;
Xaa 19 is Tyr or Gln;
Xaa 20 is Lys;
Xaa 22 is Gly, Glu, Lys, or Aib;
Xaa 23 is Gln, Glu, or Arg;
Xaa 24 is Ala or Lys;
Xaa 25 is Ala or Val;
Xaa 26 is Val, His, or Arg;
Xaa 30 is Ala, Glu, or Arg;
Xaa 31 is Trp or His;
Xaa 34 is Glu, Asn, Gly, Gln, or Arg;
Xaa 35 is Gly, Aib, or absent;
Xaa 36 is Arg, Gly, Lys, or absent;
Xaa 37 is Gly, Ala, Glu, Pro, Lys, Arg, or absent;
Xaa 38 is Ser, Gly, Ala, Glu, Gln, Pro, Arg, or absent; and
Xaa 39 is Gly or absent.
10. The derivative according to claim 1 , wherein the derivative is Chem. 54 (SEQ ID NO: 8):
or a pharmaceutically acceptable salt, amide, or ester thereof.
11. The derivative of claim 9 , wherein the linker further comprises a Glu di-radical selected from the group consisting of
and
12. The derivative of claim 4 , wherein the analogue comprises a GLP-1 analogue of Formula I (SEQ ID NO:3):
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Xaa 12 -Thr-Ser-Asp-Xaa 16 -Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Xaa 24 -Xaa 25 -Xaa 26 -Lys-Phe-Ile-Xaa 30 -Xaa 31 -Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 ,
wherein
Xaa 7 is 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 or 4-pyridylalanine;
Xaa 8 is 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, or (1-aminocyclooctyl) carboxylic acid;
Xaa 12 is Phe;
Xaa 16 is Val or Leu;
Xaa 18 is Ser, Arg, Asn, Gln, or Glu;
Xaa 19 is Tyr or Gln;
Xaa 20 is Lys;
Xaa 22 is Gly, Glu, or Aib;
Xaa 23 is Gln, Glu, or Arg;
Xaa 24 is Ala;
Xaa 25 is Ala or Val;
Xaa 26 is Val, His, or Arg;
Xaa 30 is Ala, Glu, or Arg;
Xaa 31 is Trp or His;
Xaa 34 is Glu, Asn, Gly, Gln, or Arg;
Xaa 35 is Gly, Aib, or absent;
Xaa 36 is Arg, Gly, or absent;
Xaa 37 is Gly, Ala, Glu, Pro, Arg, or absent;
Xaa 38 is Ser, Gly, Ala, Glu, Gln, Pro, Arg, or absent; and
Xaa 39 is Gly or absent.
13. The derivative of claim 12 , wherein the linker further comprises a Glu di-radical selected from the group consisting of
and
14. A pharmaceutical composition comprising a derivative according to claim 1 and a pharmaceutically acceptable excipient.
15. 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 14 .
16. A method for treating obesity in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 14 .
17. A pharmaceutical composition comprising a derivative according to claim 9 and a pharmaceutically acceptable excipient.
18. 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 17 .
19. A method for treating obesity in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 17 .
20. A pharmaceutical composition comprising a derivative according to claim 10 and a pharmaceutically acceptable excipient.
21. 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 20 .
22. A method for treating obesity in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 20 .
23. The derivative of claim 1 , wherein the amino acid sequence of the analogue is SEQ ID NO: 8.