Truncated GLP-1 derivatives and their therapeutical use

1. A GLP-1 analogue having a sequence according to formula (I)

Formula (I) 

(SEQ ID No: 2)

Xaa 7 -Xaa 8 -Xaa 9 -Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -

Ser-Xaa 18 -Tyr-Xaa 20 -Glu-Glu-Xaa 23 -Xaa 24 -Xaa 25 -Arg-

Xaa 27 -Phe-Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -R

wherein

Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;

Xaa 8 is Ala, Gly, Val, Leu, Ile, 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 9 is Glu or a Glu derivative such as alpha, alpha dimethyl-Glu;

Xaa 16 is Val or Leu;

Xaa 18 is Ser, Lys, Cys or Arg;

Xaa 20 is Leu, Lys or Cys;

Xaa 23 is Gln, Glu, Lys, Cys or Arg;

Xaa 24 is Ala or Asn;

Xaa 25 is Ala or Val;

Xaa 27 is Glu, Ala or Leu;

Xaa 30 is Ala, Glu, Lys, Arg or absent;

Xaa 31 is Trp, Lys, Cys or absent;

Xaa 33 is Val, Lys, Cys or absent;

Xaa 34 is Lys, Glu, Asn, Arg, Cys or absent;

Xaa 35 is Gly, Aib or absent;

R is amide or is absent;

provided that if Xaa 30 , Xaa 31 , Leu at position 32, Xaa 33 , or Xaa 34 is absent then each amino acid residue downstream is also absent; or

a derivative of the foregoing analogue where the analogue is derivatised at a Lys or Cys residue with an albumin binding residue or is pegylated.

2. The GLP-1 analogue according to claim 1 , wherein the amino acid at position 35 is absent, and wherein the total length of the GLP-1 analogue is 28 amino acids.

3. The GLP-1 analogue according to claim 1 , wherein the amino acids at position 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 26 amino acids.

4. The GLP-1 analogue according to claim 1 , wherein the amino acids at position 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 25 amino acids.

5. The GLP-1 analogue according to claim 1 , wherein the amino acids at position 31, 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 24 amino acids.

6. The GLP-1 analogue according to claim 1 , wherein the amino acids at position 30, 31, 32, 33, 34, and 35 are absent, and wherein the total length of the GLP-1 analogue is 23 amino acids.

7. The GLP-1 analogue according to claim 1 having a sequence according to formula (II)

Formula (II) 

(SEQ ID No: 3)

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-

Xaa 18 -Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Arg-Glu-Phe-

Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 -R

wherein

Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;

Xaa 8 is Ala, Gly, Val, Leu, Ile, 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 18 is Ser, Lys or Arg;

Xaa 30 is Ala, Glu, Lys, Arg or is absent;

Xaa 33 is Val, Lys or absent;

Xaa 34 is Lys, Glu, Arg or is absent;

Xaa 35 is Gly, Aib or is absent;

R is amide or is absent, or

a derivative of the foregoing analogue where the analogue is derivatised at a Lys or Cys residue with an albumin binding residue or is pegylated.

8. The GLP-1 analogue according to claim 1 , wherein the Lys and Cys amino acid residue is derivatized with A-B-C-D- wherein A- is selected from the group consisting of

wherein n is selected from the group consisting of 14, 15, 16 17, 18 and 19, p is selected from the group consisting of 10, 11, 12, 13 and 14, and d is selected from the group consisting of 0, 1, 2, 3, 4 and 5,

-B- is selected from the group consisting of

wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and y is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12,

-C- is selected from the group consisting of

wherein b and e are each independently selected from the group consisting of 0, 1 and 2, and c and f are each independently selected from the group consisting of 0, 1 and 2 with the proviso that b is 1 or 2 when c is 0, or b is 0 when c is 1 or 2, and e is 1 or 2 when f is 0, or e is 0 when f is 1 or 2, and

-D- is attached to said amino acid residue and is a linker.

9. The GLP-1 derivative according to claim 8 , wherein D is selected from the group consisting of

and wherein k is selected from the group consisting of 0, 1, 2, 3, 4, 5, 11 and 27, and m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6.

10. The GLP-1 analogue or derivative thereof according to claim 1 , which is selected from the following:

[Glu22,Arg26]GLP-1 (7-33) amide

N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Glu30, Lys33)GLP-1(7-33)amide;

N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Arg26,Glu30) GLP-1(7-33) amide;

[Glu22,Val25,Arg26] GLP-1 (7-33)amide;

[Aib8,Lys20,Glu22,Val25,Arg26,Glu30] GLP-1 (7-33) amide;

N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-[Aib8,Lys20,Glu22,Val25,Arg26,Glu30] GLP-1 (7-33) amide;

[Glu22, Arg26]GLP-1(7-33)peptide;

[Glu22,Val25,Arg26] GLP-1 (7-32)amide;

N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Arg26) GLP-1(7-33) amide;

N-epsilon31 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Glu22,Val25,Arg26,Lys31) GLP-1(7-33) amide;

N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(DesaminoHis7,Lys20,Glu22,Arg26) GLP-1(7-33) amide;

N-epsilon31 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(DesaminoHis7,Glu22,Arg26,Lys31)GLP-1(7-33) amide;

N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Val25,Arg26,Leu27, Glu30,Lys31)GLP-1(7-32) amide;

N-epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8, Lys20,Glu22,Val25,Arg26,Leu27,Nle30,Lys31)GLP-1(7-32) amide;

N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]-[Aib8,Glu22,Val25,Arg26,Lys31]GLP-1-(7-33) amide;

[Desamino His7,Glu22,Arg26]-GLP-1 (7-34);

[Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Lys31]GLP-1 (7-32) amide;

N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Des aminoHis7,Asp11,Glu18,Glu22,Val25,Arg26,Asp27,Glu30,Lys31]GLP-1 (7-33) amide;

[Aib8,Glu22,Val25, Lys31]GLP-1(7-33)-amide; and

N-epsilon31-{2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-N-beta34-(2-(bis-carboxymethylamino)acetyl)[Aib8,Glu22,Val25,Arg26,Lys31,Dap34] GLP-1(7-34) amide.

11. A pharmaceutical composition comprising a GLP-1 analogue or derivative thereof according to claim 1 or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient.

12. The GLP-1 analogue according to claim 1 , wherein the GLP-1 analogue comprises i) a C-terminal carboxylic acid group; or iii) a C-terminal amide group.

13. The GLP-1 analogue according to claim 1 , wherein the amino acids at position 34 and 35 are absent, and wherein the total length of the GLP-1 analogue is 27 amino acids.

14. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 11 .