Glucagon-like peptide-1 derivatives and their pharmaceutical use

1. A GLP-1 derivative which comprises a modified GLP-1(7-37) sequence having:

i) a total of 3-12 amino acid modifications as compared to GLP-1(7-37) (SEQ ID No: 1), including

a) a desamino-histidine residue at a position equivalent to position 7 of GLP-1 (7-37),

b) a Glu residue at a position equivalent to position 22 of GLP-1(7-37), and

c) an Arg residue at a position equivalent to position 26 of GLP-1(7-37); and

ii) which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 18, 20, 23, 30, 31, 34, 36 or 37 of GLP-1(7-37).

2. The GLP-1 derivative according to claim 1 , which comprises 3-8 amino acid substitutions as compared to GLP-1(7-37) (SEQ ID No: 1).

3. The GLP-1 derivative according to claim 1 , which comprises 1-3 amino acid deletions as compared to GLP-1(7-37) (SEQ ID No: 1).

4. The GLP-1 derivative according to claim 1 which comprises 1-4 amino acid additions as compared to GLP-1(7-37) (SEQ ID No: 1).

5. The GLP-1 derivative according to claim 1 , which comprises a non-natural amino acid at a position equivalent to position 8 of GLP-1(7-37) (SEQ ID No: 1).

6. The GLP-1 derivative according to claim 1 , which has an Arg residue at a position equivalent to position 34 of GLP-1(7-37) and which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 36 or 37 of GLP-1(7-37).

7. The GLP-1 derivative according to claim 1 having the sequence of 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 -Xaa 28 -Ile-Xaa 30 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -

Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -R 

wherein

(Xaa 7 -Xaa 8 ) is (desamino-histidine-alanine), or (desamino-histidine-Aib);

Xaa 9 is Glu, or a Glu derivative;

Xaa 16 is Val, or Leu;

Xaa 18 is Ser, Lys, Cys, or Arg;

Xaa 20 is Leu, or Lys;

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 28 is Phe, or a Phe derivative;

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

Xaa 31 is Trp, Cys, or Lys;

Xaa 33 is Val, Cys, or Lys;

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

Xaa 35 is Gly, Arg, Lys, Aib, or absent;

Xaa 36 is Arg, Lys, or absent;

Xaa 37 is Gly, Aib, Cys, Lys, epsilon-amino-Lys, Pro, Arg, or absent;

Xaa 38 is Lys, Glu, Arg, or absent;

Xaa 39 is Lys, Arg, or absent;

Xaa 40 is Arg, or absent;

Xaa 41 is Arg, or absent; and

R is amide, or absent;

provided that if Xaa 37 , Xaa 38 , Xaa 39 , or Xaa 40 is absent, then each amino acid residue downstream is also absent;

and which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 18, 20, 23, 30, 31, 34, 36, 37, or 39 of GLP-1(7-37) (SEQ ID No: 1).

8. The GLP-1 derivative according to claim 7 , which comprises 4-6 amino acid substitutions as compared to GLP-1(7-37) (SEQ ID No: 1).

9. The GLP-1 derivative according to claim 8 , wherein Xaa 34 is Arg.

10. The GLP-1 derivative according to claim 9 , which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 36 or 37 of GLP-1(7-37) (SEQ ID No: 1).

11. A GLP-1 derivative having the sequence of 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 -Xaa 31 -Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -

Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -R 

wherein

Xaa 7 is 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, or Arg;

Xaa 31 is Lys, or Trp;

Xaa 33 is Val, or Lys;

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

Xaa 35 is Gly, Arg, Lys, Aib, or absent;

Xaa 36 is Arg, Lys, or absent;

Xaa 37 is Gly, Aib, Lys, epsilon-amino-Lys, Pro, Arg, or absent;

Xaa 38 is Lys, Glu, Arg, or absent;

Xaa 39 is Lys, Arg, or absent;

Xaa 40 is Arg, or absent;

Xaa 41 is Arg, or absent; and

R is amide, or is absent;

provided that if Xaa 37 , Xaa 38 , Xaa 39 , or Xaa 40 is absent, then each amino acid residue downstream is also absent;

and which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 18, 20, 23, 30, 31, 34, 36, 37, or 39 of GLP-1(7-37) (SEQ ID No: 1).

12. The GLP-1 derivative according to claim 11 , which comprises 4-6 amino acid substitutions as compared to GLP-1(7-37) (SEQ ID No: 1).

13. The GLP-1 derivative according to claim 12 , wherein Xaa 34 is Arg.

14. The GLP-1 derivative according to claim 13 , which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 36 or 37 of GLP-1(7-37) (SEQ ID No: 1).

15. The GLP-1 derivative according to claim 14 , where in Xaa 7 is desamino-histidine.

16. A GLP-1 derivative which is selected from the following:

N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbon yl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;

N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-Carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);

N-epsilon37-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon37 (Polyethyleneglycol2000)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37) amide;

N-epsilon37 (3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy) ethoxy)ethoxy)ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;

N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26, Glu30,Arg34,Lys37] (GLP-1-(7-37)amide

N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys 37] (GLP-1-(7-37)amide;

N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(Octadecanoylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide

N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(19-carboxynonadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);

N-epsilon37-(2-{2-[2-((S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);

N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);

N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36]GLP-1-(7-37)-Glu-Lys peptide;

[desaminoHis7,Glu22,Arg26,Glu30,Arg34]GLP-1-(7-37)-Glu-Lys(2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl)peptide.

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

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

19. A pharmaceutical composition comprising a derivative according to claim 16 or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient.

20. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes or obesity in a subject in need thereof, the method comprising to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 17 .

21. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes or obesity in a subject in need thereof, the method comprising to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 18 .

22. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes or obesity in a subject in need thereof, the method comprising to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 19 .