Double-acylated GLP-1 derivatives

Patent metadata

Field	Value
Publication number	US-11117947-B2
Application number	US-201916692260-A
Country	US
Kind code	B2
Filing date	Nov 22, 2019
Priority date	Apr 12, 2011
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Novo Nordisk As

Inventors

• Wieczorek Birgit
• Spetzler Jane
• Kruse Thomas
• Linderoth Lars
• Kofoed Jacob

Classifications

• A61K38/26

  Glucagons · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title