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-Y a —R 2

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 IIIa

(IIIa)

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-

Z13-Z14-Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-

Z25-Leu-Z27-Z28 

wherein

Z9 is selected from Asp and Glu;

Z12 is selected from Lys, Arg and Orn;

Z13 is selected from Gln and Tyr;

Z14 is selected from Met and Leu;

Z16 is selected from Glu, Cys and Lys;

Z20 is selected from Arg, Lys and Orn;

Z24 is selected from Lys and Glu;

Z25 is selected from Trp, Lys, Cys and Phe;

Z27 is selected from Lys, Arg and Orn;

Z28 is selected from Asn and Asp or is absent;

L is a peptide sequence having the formula IIIb

(IIIb)

L1-L2-L3-L4 

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 IIIc

(IIIc)

Y12-Y13-Y14-Y15-Asp-Y17 

wherein

Y12 is selected from Tyr and Ala or is absent;

Y13 is selected from Gly and Ala or is absent;

Y14 is selected from Trp, 1Nal and Phe;

Y15 is selected from Leu, Nle, Thr and Phe; and

Y17 is selected from Phe and 3-(3-Pyridyl)-alanine.

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

3. A 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  (SEQ ID NO: 28),

Exendin-4(1-28)-K-[Leu4]Gastrin6  (SEQ ID NO: 29),

Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 33),

Exendin-4(1-28)-Peg3-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 55),

Exendin-4(1-28)-Peg3-Peg3-[Ala1,Leu4]Gastrin6  (SEQ ID NO: 56),

Exendin-4(1-28)-Peg3-Peg3-[Ala2,Leu4]Gastrin6  (SEQ ID NO: 57),

Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 58),

Exendin-4(1-28)-Peg3-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 59),

[Leu14]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 60),

[Orn12]Exendin-4(1-28)-Peg3-Peg34Leu4Gastrin6  (SEQ ID NO: 61),

[Orn27]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 62),

[Phe25]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 63),

[Asp28]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 64),

[Tyr13]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 65),

[Orn20]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 66),

Exendin-4(1-28)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 67),

Exendin-4(1-28)-[Leu4]Gastrin6  (SEQ ID NO: 68),

Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 70),

Exendin-4(1-27)-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 71),

Exendin-4(1-26)-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 72),

Exendin-4(1-27)-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 73),

[Tyr13,Leu14]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 74),

[Tyr13,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 75),

[Leu14,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 76),

[Tyr13,Leu14,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 77),

Side chain-cyclo([Lys12,Glu16]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 78),

Side chain-cyclo([Glu16,Lys20]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 79),

Side chain-cyclo([Lys20,Glu24]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 80),

[Lys16]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 81),

Exendin-4(1-28)-Peg3-K-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 82),

Exendin-4(1-28)-[Thr4]Gastrin6  (SEQ ID NO: 83),

Exendin-4(1-28)-[Phe4]Gastrin6  (SEQ ID NO: 84),

[Leu14]Exendin-4(1-28)-[1Nal3,Leu4]Gastrin6  (SEQ ID NO: 85),

[Leu14]Exendin-4(1-28)-[Nle4]Gastrin6  (SEQ ID NO: 86),

[Leu14]Exendin-4(1-28)-[Leu4,[3-(3-Pyridyl)-Ala]6]Gastrin6  (SEQ ID NO: 87),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 88),

[Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4,Phe3]Gastrin6  (SEQ ID NO: 89),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4,Phe3]Gastrin6  (SEQ ID NO: 90),

[Arg27,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 91),

[Arg12,27,Leu14,Lys16,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 92),

[Arg12,27,Leu14,Lys20,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 93),

[Arg12,27,Leu14,Lys24,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 94),

[Arg12,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 95),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-[Leu2]Gastrin4  (SEQ ID NO: 96),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 97),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 98),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Orn-[Leu2]Gastrin4  (SEQ ID NO: 99),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Orn-[Leu2]Gastrin4  (SEQ ID NO: 100),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-[Leu4]Gastrin6  (SEQ ID NO: 101),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 102),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 103),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Orn-[Leu4]Gastrin6  (SEQ ID NO: 104), and

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Orn-[Leu4]Gastrin6  (SEQ ID NO: 105).

4. A method for treatment, in a subject in need thereof, of 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, and metabolic syndrome,

the method comprising administering to said subject a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 .

5. A method according to claim 4 , wherein said subject is a human.

6. 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.

7. A method for preventing weight gain or 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 .

8. 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 .

9. The method according to claim 8 wherein the peptide conjugate or pharmaceutically acceptable salt thereof 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.

10. The method according to claim 9 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.

11. The method according to claim 9 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.

12. The method according to claim 9 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.

13. The method according to claim 9 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.

14. 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 , wherein a drug holiday dosage regimen is used.

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

16. 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.

17. 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.

18. The method according to claim 7 wherein the peptide conjugate or pharmaceutically acceptable salt thereof 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.

19. The method according to claim 18 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.

20. The method according to claim 18 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.

21. The method according to claim 18 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.

22. The method according to claim 18 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.