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 Aib residue at a position equivalent to position 8 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 has a free C-terminal carboxylic acid group.

6. The GLP-1 derivative according to claim 1 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 -Xaaz4-Xaa 24 -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 (L-histidine-Aib), (desamino-histidine-Aib), 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).

7. The GLP-1 derivative 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 -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 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 Aib;

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;

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

Xaa 35 is Gly, Arg, 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 Glu, Arg, or absent;

Xaa 39 is 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, 23, 30, 31, 34, 36 or 37 of GLP-1(7-37) (SEQ ID No: 1).

8. The GLP-derivative according to claim 1 which is selected from the following:

N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon30{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Lys30]GLP-1-(7-37);

N-epsilon31{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Lys31]GLP-1-(7-37);

N-epsilon31-(2-{2-2[2-{2-[2-((S)-3-Carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib8,Glu22,Arg26,Lys31,Arg34]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][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon20-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}eth oxy)acetyl][Aib8,Lys20,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)amide;

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}eth oxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

[Aib8,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)Lys [2-(2-{2-[4-Carboxy-4-(4-carboxy-4-{4-[4-(16-1H-tetrazol-5-yl-hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl];

N-epsilon36-(2-(2-(2-((2-[2-(2-(17-carboxyheptadecanoylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)acetyl) [Aib8,Glu22,Arg26,Glu30,Lys36]GLP-1-(7-37)Glu-amide;

N-epsilon31-[2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy]ethoxy}acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Lys31]GLP-1-(7-37);

N-epsilon20-(2-{2[2-(2-{2-[2-((S)-4-Carboxy-4-hexadecanoylamino-butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}-acetyl)[Aib8,Lys20,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);

N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;

N-epsilon37-[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,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]-[Aib8,Glu22, Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);

N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib 8,Glu22,Val25,Arg26,Lys31,Arg34,Arg35,Arg37]GLP-1-(7-37);

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,Arg34,Arg35,Arg37)]GLP-1(7-37)yl [Arg39,Arg40,Arg41];

N-epsilon31-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib 8,Glu22,Val25,Arg26,Lys31,Lys35,Lys36]GLP-1-(7-36) amide;

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; and

N-epsilon-37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy]ethoxy}acetylamino) ethoxy]ethoxy}acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1(7-37).

9. 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.

10. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a subject in need thereof, the method comprising administering to the subject therapeutically effective amount of a pharmaceutical composition according to claim 9 .

11. A pharmaceutical composition comprising a derivative according to claim 8 or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient.