GLP-1 receptor agonist peptide gastrin conjugates

• US 9,861,706 B2
• Filed: 09/24/2015
• Issued: 01/09/2018
• Est. Priority Date: 11/03/2011
• Status: Active Grant

• Current Assignee: Zealand Pharma A/S
• Original Assignee: Zealand Pharma A/S
• Inventors: Tolborg, Jakob Lind, Neerup, Trine Skovlund Ryge, Fosgerau, Keld, sterlund, Torben, Almholt, Dorthe Lennert Christensen, Larsen, Lone Frost
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/864,540
• Publication Number:
  US 20160082118A1
• Time in Patent Office: 838 Days
• Field of Search: None
• 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 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• 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: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 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

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 having the formula I

R¹-Z_a-L_a-Y_a-R² 

 

(I) (SEQ ID No;

     45)

wherein

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

R² is OH or NH₂;

Z_a is a peptide sequence having the formula Ia

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 

 

(Ia) (SEQ ID No;

     46)

wherein

Z9 is selected from Asp and Glu;

Z12 is selected from Lys, Arg and Orn;

Z13 is Tyr;

Z14 is Leu;

Z16 is selected from Glu, Arg, Orn, Cys and Lys;

Z20 is selected from Arg, Lys and Orn;

Z24 is selected from Arg, Orn, Lys and Glu;

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

Z27 is selected from Lys, Arg and Orn; and

Z28 is selected from Asn and Asp or is absent;

L_a is absent;

Y_a is a peptide sequence having the formula Ic

Y12-Y13-Trp-Y15-Asp-Phe 

 

(Ic);

(SEQ ID NO;

     62)

wherein

Y12 is selected from Tyr and Ala or is absent;

Y13 is selected from Gly and Ala or is absent; and

Y15 is selected from Leu and Thr; and

wherein at least one of Lys, Orn or Cys in formula Ia is further conjugated to a lipophilic and/or a biotinyl substituent and/or pegylated;

or a pharmaceutically acceptable salt thereof.

2. A peptide conjugate according to claim 1 wherein

Z_a is a peptide sequence having the formula IIa

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Lys-Z13-Z14-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 

 

(IIa) (SEQ ID NO;

     48)

wherein

Z9 is selected from Glu and Asp;

Z13 is Tyr;

Z14 is Leu;

Z16 is selected from Glu, Cys and Lys;

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

Z28 is selected from Asn and Asp or is absent;

Y_a is a peptide sequence having the formula IIc

Tyr-Gly-Trp-Y15-Asp-Phe 

 

(IIc) (SEQ ID NO;

     49)

wherein

Y15 is selected from Leu and Thr; and

wherein at least one of Lys or Cys in position Z16 or Z25 of formula IIa is further conjugated to a lipophilic and/or a biotinylic substituent and/or pegylated;

or a pharmaceutically acceptable salt thereof.

3. A peptide conjugate or a pharmaceutically acceptable salt thereof according to claim 1 wherein the sequence of the peptide of formula I is selected from:

H-HGEGTFTSELSKYLE-K(hexadecanoyl-isoGlu)-EAVRLFIEFLKNYGWLDF-NH₂ 

 

(SEQ ID NO;

     27);

H-HGEGTFTSELSKYLE-K(hexadecanoyl-isoGlu)-EAVRLFIEFLKNWLDF-NH₂ 

 

(SEQ ID NO;

     28);

H-HGEGTFTSELSKYLE-K(hexadecanoyl-isoGlu)-EAVRLFIEFLKYGWLDF-NH₂ 

 

(SEQ ID NO;

     31);

H-HGEGTFTSELSKYLE-K(hexadecanoyl-isoGlu)-EAVRLFIEFLKWLDF-NH₂ 

 

(SEQ ID NO;

     32);

H-HGEGTFTSELSKYLEEEAVRLFIE-K(hexadecanoyl-isoGlu)-LKNYGWLDF-NH₂ 

 

(SEQ ID NO;

     36); and

H-HGEGTFTSELSKYLEEEAVRLFIE-K(hexadecanoyl-isoGlu)-LKDYGWLDF-NH₂ 

 

(SEQ ID NO;

     37).

7. A method of inducing β

-cell neogenesis, islet neogenesis, β

-cell survival, and/or β

-cell proliferation and/or inhibiting β

-cell apoptosis and/or necrosis in the pancreatic islets in a subject in need thereof comprising administering to said subject a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1.

8. A method of treating or inhibiting the development of a disease or disorder selected from the group consisting of:

obesity, 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, macrovascular disease, coronary heart disease, peripheral artery disease, stroke, microvascular disease, gastric disease, metabolic syndrome, cancer, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, and kidney failure

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

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

10. A method of inhibiting weight gain, promoting weight loss, improving circulating glucose levels, improving glucose tolerance, improving circulating cholesterol levels, lowering circulating LDL levels, increasing an HDL/LDL ratio, and/or treating a condition caused or characterized by excess body weight in a subject in need thereof comprising administering to said subject a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1.

11. The method of claim 8, wherein the peptide conjugate or pharmaceutically acceptable salt thereof is administered as part of a combination therapy with a proton pump inhibitor or an agent for treating or inhibiting diabetes, obesity, dyslipidemia, or hypertension.

12. The method of claim 11, wherein the agent for treating or inhibiting diabetes is metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin or an insulin analogue.

13. The method of claim 11, wherein the agent for treating or inhibiting obesity is a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist.

14. The method of claim 11, wherein the agent for treating or inhibiting hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker.

15. The method of claim 11, wherein the agent for treating or inhibiting-dyslipidaemia is a statin, a fibrate, a niacin and/or a cholesterol absorption inhibitor.

16. The method of claim 11, wherein the proton pump inhibitor is an agent of the benzimidazole derivative type or of the imidazopyridine derivative type.

17. A method of synthetically manufacturing a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 by solid phase or liquid phase peptide synthesis techniques.

18. A device comprising at least one peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 for delivering the at least one peptide conjugate or pharmaceutically acceptable salt thereof to a subject.

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

4. A peptide conjugate having the formula III

R¹-Z_b-L_b-Y_b-R² 

 

(III) (SEQ ID No;

     50)

wherein

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

R² is OH or NH₂;

Z_b is a peptide sequence having the formula IIIa

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 

 

(IIIa) (SEQ ID NO;

     51)

wherein

Z25 is selected from Phe and Trp; and

Z28 is selected from Asn and Asp or is absent;

L_b is absent;

Y_b is a peptide sequence having the formula IIIc

Y10-Y11-Tyr-Gly-Trp-Y15-Asp-Phe 

 

(IIIc) (SEQ ID NO;

     52)

wherein

Y10 is Glu or is absent;

Y11 is Ala or is absent; and

Y15 is selected from Leu and Thr;

or a pharmaceutically acceptable salt thereof;

provided that formula III is not

H-HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF-NH₂ 

 

(SEQ ID NO;

     54).

5. A peptide conjugate according to claim 4 wherein

Z_b is a peptide sequence having the formula IVa

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Asn 

 

(IVa) (SEQ ID NO;

     57)

wherein

Z25 is selected from Phe and Trp; and

Y_b is a peptide sequence having the formula IVc

Tyr-Gly-Trp-Y15-Asp-Phe 

 

(IVc) (SEQ ID NO;

     58)

wherein

Y15 is selected from Leu and Thr;

or a pharmaceutically acceptable salt thereof.

6. A peptide conjugate or a pharmaceutically acceptable salt thereof according to claim 4 wherein the sequence of the peptide of formula III is selected from

H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH₂ 

 

(SEQ ID NO;

     12);

H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH₂ 

 

(SEQ ID NO;

     16);

H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH₂ 

 

(SEQ ID NO;

     17);

H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH₂ 

 

(SEQ ID NO;

     20);

H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH₂ 

 

(SEQ ID NO;

     21);

H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH₂ 

 

(SEQ ID NO;

     22);

H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH₂ 

 

(SEQ ID NO;

     23); and

H-HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF-NH₂ 

 

(SEQ ID NO;

     24).