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

• US 9,649,362 B2
• Filed: 06/10/2015
• Issued: 05/16/2017
• Est. Priority Date: 04/27/2010
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Neerup, Trine Skovlund Ryge, Tolborg, Jakob Lind, Fosgerau, Keld, sterlund, Torben, Martensson, Ulrika, Brorson, Marianne, Rolsted, Kamilla
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/735,738
• Publication Number:
  US 20160184400A1
• Time in Patent Office: 706 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2207 Gastrins; Cholecystokinins [CCK]
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/463 : from amphibians
• CPC Class Codes: C07K 14/575 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/57563 : Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 14/595 : Gastrins; Cholecystokinins [CCK]
• CPC Class Codes: C07K 14/605 : Glucagons

Abstract

The present invention relates, inter alia, to certain peptide conjugates, and to the use of the conjugates in the treatment of a variety of diseases or disorders, including diabetes (type 1 and/or type 2) and diabetes-related diseases or disorders.

Claims

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

R¹—

Z_a-L-Y_a—

R²

wherein

R¹ is H, C_1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;

R² is OH or NH₂;

Z_a is a peptide sequence having the formula IIIa

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.