NOVEL A4B7 PEPTIDE ANTAGONISTS

• US 20140294902A1
• Filed: 03/28/2014
• Published: 10/02/2014
• Est. Priority Date: 04/02/2013
• Status: Abandoned Application

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Mattheakis, Larry C.
• Application Number:
  US14/229,799
• Publication Number:
  US 20140294902A1
• Time in Patent Office: Days
• US Class Current: 424/400
• 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: 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 11/14 Antitussive agents
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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: A61P 5/50 for increasing or potentiating the activity of insulin
• 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

Abstract

The invention relates to disulfide-rich peptide molecules which inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, and show high selectivity against α4β1 binding.

Claims

1. A peptide molecule comprising Formula (I)

Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴, or a pharmaceutically acceptable salt thereof, wherein

Xaa¹ is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid;

Xaa² is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid;

Xaa³ is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Met, Thr, Ser, a suitable isostere, and a corresponding D-amino acid;

Xaa⁴ is selected from the group consisting of Cys, Asp, Glu, Lys, Pen, HGlu, HLys, Orn, Dap, Dab, β

Asp, β

Glu, HGlu, HLys, a suitable isostere, and a corresponding D-amino acid;

Xaa⁵ is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Tyr, Trp, Met, Thr, HArg, 4-Guan, Cit, Cav, Dap, Dab, Phe(4-NH2), a suitable isostere, and a corresponding D-amino acid;

Xaa⁶ is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Thr, Trp, Tyr, Met, a suitable isostere replacement and a corresponding D-amino acid;

Xaa⁷ is selected from the group consisting of Asp, and a suitable isostere replacement;

Xaa⁸ is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Val, Tyr, Trp, Leu, Met, a suitable isostere, and a corresponding D-amino acid;

Xaa⁹ 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, HCha, a suitable isostere, and a corresponding D-amino acid;

Xaa¹⁰ is selected from the group consisting of Cys, Asp, Lys, Glu, Pen, HAsp, HGlu, HLys, Orn, Dap, Dab, HLys, a suitable isostere, and a corresponding D-amino acid;

Xaa¹¹ 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), dihydro-Trp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, Bip, Ala(3,3 diphenyl), Biphenyl-Ala, D-Phe, D-Trp, D-Tyr, D-Glu, D-His, D-Lys, 3,3-diPhe, β

-HTrp, F(4-CF3), O-Me-Tyr, 4-Me-Phe, an aromatic ring substituted Phe, an aromatic ring substituted Trp, an aromatic ring substituted His, a hetero aromatic amino acid, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, a corresponding D-amino acid;

a suitable isostere; and

a suitable linker moiety.

Xaa¹² is selected from the group consisting of absent, Glu, Lys, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, Asp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, β

-HGlu, 2-Nal, 1-Nal, Bip, β

-HPhe, β

Glu, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;

Xaa¹³ is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, absent, a suitable isostere, and a corresponding D-amino acid; and

Xaa¹⁴ is selected from the group consisting of absent, a natural amino acid, a suitable isostere, and a corresponding D-amino acid,

wherein the peptide further comprises a bond selected from the group consisting of a disulfide bond and a lactam bond between Xaa⁴ and Xaa¹⁰.

2. The peptide molecule of claim 1 further comprising a 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, heteroaromatic acids

3. The peptide molecule of claim 2, wherein the N-terminus of the peptide molecule further comprises the modifying group.

4. The peptide molecule of claim 2, wherein the C-terminus of the peptide molecule further comprises the modifying group.

5. The peptide molecule of claim 1, further comprising a disulfide bond between Xaa⁴ and Xaa¹⁰.

6. The peptide molecule of claim 1, further comprising a lactam bond between Xaa⁴ and Xaa¹⁰.

7. The peptide molecule of claim 1, further comprising N(alpha)methylation at one or more positions selected from the group consisting of Xaa³, Xaa⁵, Xaa⁷-Xaa⁹, and Xaa¹¹-Xaa¹³.

8. The peptide molecule of claim 1, further comprising acylation at one or more position selected from the group consisting of Xaa¹-Xaa³ and Xaa¹¹-Xaa¹⁴.

9. The peptide molecule of claim 1, wherein when Xaa¹⁰ is selected from the group consisting of Asp, HAsp, Glu, and HGlu, HLys, Xaa⁴ is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGlu, and when Xaa¹⁰ is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGlu, Xaa⁴ is selected from the group consisting of Asp, HAsp, Glu, HGlu, and HLys.

10. The peptide molecule of claim 9, further comprising a lactam bond between Xaa⁴ and Xaa¹⁰.

11. The peptide molecule of claim 1, wherein when Xaa⁴ is selected from the group consisting of Asp, HAsp, Glu, HGlu, and HLys, and when Xaa¹⁰ is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGlu, Xaa⁴ and Xaa¹⁰ are cyclized through an amide bond.

12. A method for treating inflammatory bowel disease in a patient, comprising administering to the patient an effective amount of a peptide molecule of claim 1.

13. The method of claim 12, wherein the inflammatory bowel disease is ulcerative colitis.

14. The method of claim 12, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

15. The method of claim 12, wherein the peptide molecule inhibits binding of α

4β

7 to MAdCAM.

16. A method for treating a human having an inflammatory bowel disease, comprising the steps of administering to the human an effective amount of a peptide molecule according to the composition of claim 1.

17. The method of claim 16, further comprising a step wherein the peptide molecule is administered 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.

18. The method of claim 16, wherein the effective amount of peptide molecule is sufficient to achieve at least one of the following selected from the group consisting of:

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.

19. The method of claim 16, wherein the peptide molecule is administered orally.

20. The method of claim 16, wherein the peptide molecule is administered parenterally.

21. The method of claim 16, wherein the peptide molecule is administered topically.

22. The method of claim 16, wherein the peptide molecule is selected from the group consisting of SEQ ID NO:

39-146.

23. The method of claim 16, further comprising a step for administering the peptide molecule to the human at an interval sufficient to ameliorate the inflammatory bowel disease.

24. A method for treating a human afflicted with a condition that is associated with a biological function of α

4β

7, the method comprising administering to the human a peptide molecule according to the composition of claim 1.

25. The method of claim 24, further comprising a step for administering the peptide molecule to the human at an interval sufficient to ameliorate the condition.

26. The method of claim 25, wherein the interval is selected from the group consisting of around the clock, hourly, every four hours, once daily, twice daily, three times daily, four times daily, every other day, weekly, bi-weekly, and monthly.

27. A method for stabilizing a peptide molecule according to claim 1, the method comprising a step for substituting Xaa⁴ and Xaa¹⁰ with an amino acid residue selected from the group consisting of Cys and Pen, wherein Xaa⁴ and Xaa¹⁰ form a cyclized structure through a disulfide bond.

28. A method for stabilizing a peptide molecule of Formula (II)

Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰, or a pharmaceutically acceptable salt thereof, wherein the method comprises a step for substituting Xaa¹ and Xaa⁷ with compatible amino acid residues that are capable of forming a cyclized structure through a bond selected from the group consisting of an amide bond and a disulfide bond.

29. The method of claim 28, wherein the compatible amino acids are selected from the group consisting of Cys and Pen, wherein Xaa¹ and Xaa⁷ form a cyclized structure through a disulfide bond.

30. The method of claim 28, wherein when Xaa⁴ is selected from the group consisting of Lys, HLys, Orn, Dap, and Dab, and when Xaa¹⁰ is selected from the group consisting of Asp, Glu, HGlu, β

-Asp, and β

-Glu, Xaa⁴ and Xaa¹⁰ are cyclized through an amide bond.

31. A pharmaceutical composition comprising a peptide molecule according to at least one of Formula (I) and Formula (II).

32. The composition of claim 31, further comprising an enteric coating.

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

34. A method for treating a condition in a subject comprising administering the pharmaceutical composition of claim 32 to the subject, wherein the condition is treatable by reducing the activity (partially or fully) of α

4β

7 in the subject.

35. The method of claim 34, wherein the subject is a human being.

36. The method of claim 34, wherein the condition is an inflammatory condition of the gastrointestinal system.

37. A method for treating a human afflicted with a condition that is associated with a biological function α

4β

7 and comprising administering to the individual a peptide molecule of Formula (I) in an amount sufficient to inhibit (partially or fully) the biological function of α

4β

7 to tissues expressing MAdCAM.

39. The method of claim 37, wherein the condition is inflammatory bowel disease.

40. The method of claim 37, wherein the condition is selected from the group consisting of Inflammatory Bowel Disease (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, and graft versus host disease.

41. The method of claim 37, wherein the peptide molecule is administered to the individual by a form of administration selected from the group consisting of oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, vaginal, and topical.

38. A method for treating a human afflicted with a condition that is associated with a biological function of α

4β

7 and comprising administering to the individual a peptide molecule of Formula (I) in an effective amount sufficient to at least partially inhibit the biological function of α

4β

7 to tissues expressing MAdCAM.

42. A method for treating an individual with an α

4β

7 integrin antagonist peptide molecule according to at least one of Formula (I) and Formula (II), wherein the α

4β

7 integrin antagonist peptide molecule comprises an increased half-life.

43. The method of claim 42, wherein the increased half-life is at least one day in vitro or in vivo.

44. The method of claim 42, wherein when the increased half-life is equal to or greater than a period consistent with no more frequent than twice daily dosing in vivo, the α

4β

7 integrin antagonist peptide molecule comprises a pharmaceutical preparation that is administered orally.

45. The method of claim 42, wherein when the increased half-life is from approximately 12 hours to greater than 24 in vivo, the α

4β

7 integrin antagonist peptide molecule comprises a pharmaceutical preparation that is administered parenterally.

46. The method of claim 42, wherein when the increased half-life is from approximately 12 hours to greater than 24 hours in vivo, the α

4β

7 integrin antagonist peptide molecule comprises a pharmaceutical preparation that is administered topically.

47. A method for increasing SIF stability of a peptide molecule according to SEQ ID NOs:

1-146, comprising a step for substituting N-Me-Arg for one or more unmethylated arginine residues.

48. A method for increasing SIF stability of a peptide molecule according to SEQ ID NOs:

1-146, comprising a step for substituting Pen for one or more cysteine residues.

49. A method for increasing redox stability of a peptide molecule according to SEQ ID NOs:

1-146, comprising a step for substituting Pen for one or more cysteine residues.