NOVEL a4B7 THIOETHER PEPTIDE DIMER ANTAGONISTS

• US 20190016756A1
• Filed: 07/19/2018
• Published: 01/17/2019
• Est. Priority Date: 05/16/2014
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Zemede, Genet, Frederick, Brian Troy, Mattheakis, Larry C., Liu, David
• Granted Patent: US 10,626,146 B2
• Time in Patent Office: Days
• 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 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• 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 47/64 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/70546 : Integrin superfamily
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 : having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/56 : the cyclisation not occurring through 2,4-diamino-butanoic acid

Abstract

The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.

Claims

1-19. -19. (canceled)

20. A peptide molecule comprising a structure of Formula (VI):

Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹ 

 

(Formula VI)

or a pharmaceutically acceptable salt thereof, wherein

Xaa¹ is a 2-Me-benzoyl group capable of forming a thioether bond with Xaa⁷;

Xaa² is selected from the group consisting of N(alpha)-Me-Arg, Arg, HArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, 4-Guan, Cit, Cav, and suitable isostere replacements;

Xaa³ is selected from the group consisting of Ser, Gly, and suitable isostere replacements;

Xaa⁴ is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements;

Xaa⁵ is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr, and suitable isostere replacements;

Xaa⁶ is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, N-Me-Leu, and suitable isostere replacements;

Xaa⁷ is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, and D-Pen;

Xaa⁸ is selected from the group consisting of absent, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Ser, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, HPhe, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β

-Me-Phe, 4-Me-Phe, and corresponding D-amino acids and suitable isostere replacements;

Xaa⁹ is selected from the group consisting of absent, Glu, Amide, Lys, COOH, CONH₂, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, β

-HGlu, 2-Nal, 1-Nal, D-Asp, Bip, β

-HPhe, β

-Glu, D-Tyr, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, Glu, N-Me-Asp, alpha-H-Glu, suitable isosteres, and corresponding D-amino acids;

Xaa¹⁰ is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH₂, suitable isosteres, and corresponding D-amino acids; and

Xaa¹¹ is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH₂, suitable isosteres, and corresponding D-amino acids, wherein the peptide further comprises a thioether bond between Xaa¹ and Xaa⁷, wherein the peptide further comprises a thioether bond between Xaa¹ and Xaa⁷.

21. The peptide molecule or pharmaceutically acceptable salt thereof of claim 20, wherein Xaa⁴ is a 2-methyl benzoyl moiety that forms a thioether bond with Xaa¹⁰, Xaa⁵ is N-Me-Arg, Xaa⁶ is Ser, Xaa⁷ is Asp, Xaa⁸ is Thr, Xaa⁹ is Leu, and Xaa¹⁰ is Pen, Cys, D-Cys or HomoCys.

22. The peptide molecule or pharmaceutically acceptable salt thereof of claim 21, wherein Xaa¹⁰ is Pen or Cys.

23. The peptide molecule or pharmaceutically acceptable salt thereof of claim 20, further comprising a terminal modifying group selected from the group consisting of DIG, PEG4, PEG13, PEG25, PEG1K, PEG2K, PEG4K, PEG5K, Polyethylene glycol having molecular weight from 400 Da to 40,000 Da, IDA, Ac-IDA, ADA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, AADA, suitable aliphatic acids, suitable aromatic acids, and heteroaromatic acids.

24. The peptide molecule of claim 20, wherein the C-terminus of the peptide molecule further comprises a modifying group.

25. The peptide molecule or pharmaceutically acceptable salt thereof of claim 20, wherein the peptide molecule is a monomer.

26. The peptide molecule or pharmaceutically acceptable salt thereof of claim 20, wherein the peptide molecule is a dimer.

27. The peptide molecule or pharmaceutically acceptable salt thereof of claim 26, comprising two peptide molecules dimerized by a linker.

28. The peptide molecule or pharmaceutically acceptable salt thereof of claim 27, where in the linker is selected from the group consisting of:

DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, Triazine, Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da.

29. The peptide molecule or pharmaceutically acceptable salt thereof of claim 27, wherein the two peptide molecules are dimerized via their C-termini.

30. A pharmaceutical composition comprising the peptide molecule or pharmaceutically acceptable salt thereof of claim 20 and a pharmaceutically acceptable carrier, diluent or excipient.

31. The pharmaceutical composition of claim 30, wherein the pharmaceutical composition is formulated for oral delivery.

32. The pharmaceutical composition of claim 30, further comprising an enteric coating.

33. The pharmaceutical composition of claim 32, wherein the enteric coating releases the pharmaceutical composition within a subject'"'"'s lower gastrointestinal system.

34. A method for treating or preventing a disease or condition that is associated with a biological function of integrin α

4β

7, the method comprising providing to a subject in need thereof an effective amount of the peptide molecule or pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 20.

35. The method of claim 34, wherein the disease or condition is selected from the group consisting of Inflammatory Bowel Disease (IBD), adult IBD, pediatric IBD, adolescent IBD, ulcerative colitis, Crohn'"'"'s disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiotherapy, chemotherapy, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, primary sclerosing cholangitis, human immunodeficiency virus (HIV) infection in the GI tract, eosinophilic asthma, eosinophilic esophagitis, gastritis, colitis, microscopic colitis and graft versus host disease (GVHD).

36. The method of claim 34, wherein the disease or condition is an inflammatory bowel disease, ulcerative colitis, or Crohn'"'"'s disease.

39. The method of claim 34 wherein the peptide molecule or pharmaceutically acceptable salt thereof inhibits binding of α

4β

7 to MAdCAM.

40. The method of claim 34, wherein the peptide molecule or pharmaceutically acceptable salt thereof or the pharmaceutical composition is provided to the subject in need thereof at an interval sufficient to ameliorate the condition.

42. The method of claim 34, wherein the peptide molecule or pharmaceutically acceptable salt thereof or pharmaceutical composition is provided as an initial does followed by one or more subsequent doses, and the minimum interval between any two doses is a period of less than 1 day, and wherein each of the doses comprises an effective amount of the peptide molecule or pharmaceutically acceptable salt thereof.

43. The method of claim 34, wherein the effective amount of the peptide molecule or pharmaceutically acceptable salt thereof or the pharmaceutical composition is sufficient to achieve at least one of the following:

a) about 50% or greater saturation of MAdCAM binding sites on α

4β

7 integrin molecules;

b) about 50% or greater inhibition of α

4β

7 integrin expression on the cell surface; and

c) about 50% or greater saturation of MAdCAM binding sites on α

4β

7 molecules and about 50% or greater inhibition of α

4β

7 integrin expression on the cell surface, wherein i) the saturation is maintained for a period consistent with a dosing frequency of no more than twice daily;

ii) the inhibition is maintained for a period consistent with a dosing frequency of no more than twice daily;

or iii) the saturation and the inhibition are each maintained for a period consistent with a dosing frequency of no more than twice daily.

44. The method of claim 34, wherein the peptide molecule or pharmaceutically acceptable salt thereof is administered orally.

37-38. -38. (canceled)

41. (canceled)

45-46. -46. (canceled)