Peptide conjugates of GLP-1 receptor agonists and gastrin and their use

1. A peptide conjugate or pharmaceutically acceptable salt thereof having the formula

R 1 —Z a -L a -Y a —R 2   (I)

wherein

R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R 2 is OH or NH 2 ;

Z a is a peptide sequence having the formula IVa

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-Gln-Met-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Z27-Z28  (IVa)

wherein

Z9 is selected from Glu and Asp;

Z12 is selected from Lys and Orn;

Z16 is selected from Glu and Lys;

Z27 is selected from Lys and Orn;

Z28 is selected from Asn and Asp or is absent;

L a is a sequence having the formula IVb

L1-L2-L3-L4  (IVb)

wherein

L1 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;

L2 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;

L3 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;

L4 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;

Y a is a peptide sequence having the formula IVc

Y12-Y13-Trp-Leu-Asp-Phe  (IVc)

wherein

Y12 is Tyr or is absent; and

Y13 is Gly or is absent.

2. The peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z12 is Lys and Z16 is Glu, and wherein said residues form an intramolecular bridge.

3. The peptide conjugate or pharmaceutically acceptable salt thereof according to claim 2 , wherein the intramolecular bridge is a lactam ring.

4. The peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z a has at least 85% identity to native exendin-4, e.g. at least 90 or 95%.

5. The peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 , wherein the peptide of formula I is selected from the group consisting of:

Exendin-4(1-28)-[Leu4]Gastrin6,

Exendin-4(1-28)-K-[Leu4]Gastrin6, and

Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6.

6. The peptide conjugate or pharmaceutically acceptable salt thereof according to claim 5 , wherein the peptide of formula I is selected from the group consisting of:

Exendin-4(1-28)-Peg3-Peg3-[Leu3]Gastrin5,

Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6,

Exendin-4(1-28)-Peg3-Peg3-[Leu2]Gastrin4,

[Orn12]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6,

[Orn27]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6,

[Asp28]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6,

Exendin-4(1-28)-Peg3-[Leu4]Gastrin6,

Exendin-4(1-28)-[Leu4]Gastrin6,

Exendin-4(1-27)-Peg3-[Leu4]Gastrin6,

Exendin-4(1-27)-Peg3-[Leu3]Gastrin5,

Exendin-4(1-27)-Peg3-[Leu2]Gastrin4,

[Lys16]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6, and

Exendin-4(1-28)-Peg3-K-Peg3-[Leu4]Gastrin6.

7. A method of treating a disease or disorder selected from the group consisting of: type 1 diabetes, type 2 diabetes, pre-diabetes, Insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, hyperglycemia, hypertension, atherogenic dyslipidemia, arteriosclerosis (e.g. atherosclerosis), coronary heart disease, peripheral artery disease, stroke, microvascular disease, gastric disease, metabolic syndrome, cancer (e.g. colon cancer), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 .

8. A method according to claim 7 , wherein said subject is a human.

9. A pharmaceutical composition comprising a peptide conjugate, or pharmaceutically acceptable salt thereof, according to claim 1 , together with a pharmaceutically acceptable carrier, excipient or vehicle.

10. A method for promoting weight loss in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 .

11. A method of improving circulating glucose levels, glucose tolerance and/or circulating cholesterol levels, lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 .

12. The method according to claim 7 , wherein the compound is administered as part of a combination therapy with an agent for treatment of a condition selected from the group consisting of: diabetes, obesity, dyslipidaemia, or hypertension.

13. The method according to claim 12 wherein the agent for treatment of diabetes is selected from the group consisting of: metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin and an insulin analogue.

14. The method according to claim 12 wherein the agent for treatment of obesity is selected from the group consisting of a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, and melanin concentrating hormone receptor 1 antagonist.

15. The method according to claim 12 wherein the agent for treatment of hypertension is selected from the group consisting of an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, and calcium channel blocker.

16. The method according to claim 12 wherein the agent for treatment of dyslipidaemia is selected from the group consisting of a statin, a fibrate, a niacin and a cholesterol absorption inhibitor.

17. The method of improving circulating glucose levels, glucose tolerance and/or circulating cholesterol levels, lowering circulating LDL levels, and/or increasing HDL/LDL ratio in an individual in need thereof, said method comprising administering to said individual a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 , wherein a drug holiday dosage regimen is used.

18. A process for manufacturing a compound according to claim 1 , wherein said manufacture is by peptide synthesis or recombinant synthesis.

19. A device comprising at least one peptide conjugate, or pharmaceutically acceptable salt thereof, according to claim 1 , for delivery of the peptide conjugate to a subject.

20. A kit comprising at least one peptide conjugate, or pharmaceutically acceptable salt thereof, according to claim 1 , and further comprising packaging or instructions for use.

21. The method of claim 10 , wherein the compound is administered as part of a combination therapy with an agent for treatment of a condition selected from the group consisting of diabetes, obesity, dyslipidaemia, and hypertension.

22. The method of claim 21 , wherein the agent for treatment of diabetes is selected from the group consisting of metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin, and an insulin analogue.

23. The method of claim 21 , wherein the agent for treatment of obesity is selected from the group consisting of a glucagon-like peptide receptor 1 agonist, peptide YY and analogues thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, and melanin concentrating hormone receptor 1 antagonist.

24. The method of claim 21 , wherein the agent for treatment of hypertension is selected from the group consisting of an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, and calcium channel blocker.

25. The method of claim 11 , wherein the compound is administered as part of a combination therapy with an agent for treatment of a condition selected from the group consisting of diabetes, obesity, dyslipidaemia, and hypertension.

26. The method of claim 25 , wherein the agent for treatment of diabetes is selected from the group consisting of metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin, and an insulin analogue.

27. The method of claim 25 , wherein the agent for treatment of obesity is selected from the group consisting of a glucagon-like peptide receptor 1 agonist, peptide YY and analogues thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, and melanin concentrating hormone receptor 1 antagonist.

28. The method of claim 25 , wherein the agent for treatment of hypertension is selected from the group consisting of an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, and calcium channel blocker.

29. The method of claim 25 , wherein the agent for treatment of dyslipidaemia is selected from the group consisting of a statin, a fibrate, a niacin, and a cholesterol absorption inhibitor.

30. The process according to claim 19 , wherein said manufacture is by peptide synthesis.

31. The process according to claim 18 , wherein said manufacture is by recombinant synthesis.