NOVEL a4B7 PEPTIDE DIMER ANTAGONISTS

• US 20140193465A1
• Filed: 10/10/2013
• Published: 07/10/2014
• Est. Priority Date: 10/11/2012
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Patel, Dinesh V., Mattheakis, Larry C., Bhandari, Ashok
• Granted Patent: US 9,273,093 B2
• 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 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: C07K 14/47 from mammals
• 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

Abstract

The invention relates to disulfide-rich dimer 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 dimer compound comprising two peptide monomer subunits of Formula (I)

Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹²-Xaa¹³-Xaa¹⁴-Xaa¹⁵ 

 

(I),

or a pharmaceutically acceptable salt thereof, wherein

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

Xaa² is selected from the group consisting of Ac-, NH₂, a suitable linker moiety, absent, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;

Xaa³ is selected from the group consisting of Ac-, NH₂, a suitable linker moiety, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;

Xaa⁴ is selected from the group consisting of Cys, Pen, Asp, Glu, hGlu, Lys, homo-Lys, Orn, Dap, Dab, 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, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, homo-Arg, Dap, Dab, N-Me-Arg, Arg-(Me)sym, Arg-(me)asym, 4-Guan, Cit, Cav, 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, Asn, Glu, Leu, Val, Tye, Trp, Met, a suitable isostere replacement and a corresponding D-amino acid;

Xaa⁷ is selected from the group consisting of Asp, N-Me-Asp, a suitable isostere replacement for Asp, and a corresponding D-amino acid;

Xaa⁸ is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tye, Trp, Met, an N-Methyl amino acid;

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, Asn, Glu, Val, homo-Leu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, N-Me-Leu, a suitable isostere, and a corresponding D-amino acid;

Xaa¹⁰ is selected from the group consisting of Cys, Asp, Pen, Lys, homo-Lys, Orn, GluDap, Dab, a suitable isostere, and a corresponding D-amino acid;

Xaa¹¹ is selected from the group consisting of Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, CONH₂, His, Glu, Ser, Arg, Pro, Phe, Sar, 1Nal, 2Nal, 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, 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 Glu, Amide, Lys, COOH, CONH₂, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;

Xaa¹³ is selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, COOH, CONH₂, NH₂, absent, a suitable linker moiety, a suitable isostere, and a corresponding D-amino acid;

Xaa¹⁴ is selected from the group consisting of a natural amino acid, absent, COOH, CONH₂, NH₂, a suitable isostere, a suitable linker, a corresponding D-amino acid, and an N-Methyl amino acid; and

Xaa¹⁵ is selected from the group consisting of a suitable linker, and absent.

2. The peptide dimer compound of claim 1, wherein when Xaa¹ is absent, Xaa² is selected from the group consisting of Ac, NH₂ and a suitable linker.

3. The peptide dimer compound of claim 1, wherein when Xaa¹ and Xaa² are absent, Xaa³ is selected from the group consisting of Ac, NH₂ and a suitable linker.

4. The peptide dimer compound of claim 1, wherein when Xaa¹⁰ is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, Xaa⁴ is selected from the group consisting of Asp, Glu, and hGlu, and when Xaa¹⁰ is selected from the group consisting of Asp, Glu, and hGlu, Xaa⁴ is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab.

5. The peptide dimer compound of claim 1, wherein when Xaa⁴ and Xaa¹⁰ are selected from the group consisting of Cys and Pen, Xaa⁴ and Xaa¹⁰ are cyclized through a disulfide bond.

6. The peptide dimer compound of claim 1, wherein when Xaa⁴ is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, and when Xaa¹⁰ is selected from the group consisting of Asp, Glu, and hGlu, Xaa⁴ and Xaa¹⁰ are cyclized through an amide bond.

7. The peptide dimer compound of claim 1, wherein the suitable linker is selected from the group consisting of DIG, DIG-OH, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, suitable aromatics, heteroaromatics, and polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da.

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

9. The method of claim 8, wherein the inflammatory bowel disease is ulcerative colitis.

10. The method of claim 8, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

11. The method of claim 8, wherein the peptide dimer compound inhibits binding of α

4β

7 to MAdCAM.

12. 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 dimer according to the composition of claim 1.

13. The method of claim 12, further comprising a step wherein the peptide dimer 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 dimer.

14. The method of claim 12, wherein the effective amount of peptide dimer 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;

15. The method of claim 12, wherein the peptide dimer is administered orally.

16. The method of claim 12, wherein the peptide dimer is administered parenterally.

17. The method of claim 12, wherein the peptide dimer is administered topically.

18. The method of claim 12, wherein the peptide dimer is selected from the group consisting of SEQ ID NO:

39-136.

19. The method of claim 12, further comprising a step for administering the peptide dimer to the human at an interval sufficient to ameliorate the inflammatory bowel disease.

20. 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 dimer according to the composition of claim 1.

21. The method of claim 20, further comprising a step for administering the peptide dimer to the human at an interval sufficient to ameliorate the condition.

22. The method of claim 21, 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.

23. A method for stabilizing a peptide dimer compound 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.

25. The method of claim 23, wherein the compatible amino acids are selected from the group consisting of Cys and Pen, wherein Xaa⁴ and Xaa¹⁰ form a cyclized structure through a disulfide bond.

24. A method for stabilizing a peptide dimer compound of Formula (II)

Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰-Xaa¹¹-Xaa¹² 

 

(II),

or a pharmaceutically acceptable salt thereof, wherein the method comprises a step for substituting Xaa⁴ and Xaa¹⁰ with compatible amino acid residues that are capable of forming a cyclized structure through at least one of an amide bond and a disulfide bond.

26. The method of claim 24, wherein when Xaa⁴ is selected from the group consisting of Lys, homo-Lys, 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.

27. A pharmaceutical composition comprising a peptide dimer compound according to at least one of Formula (I) and Formula (II).

28. The composition of claim 27, further comprising an enteric coating.

29. The composition of claim 28, wherein the enteric coating protects and releases the pharmaceutical composition with a subjects lower gastrointestinal system.

30. A method for treating a condition in a subject comprising administering the pharmaceutical composition of claim 27 to the subject, wherein the condition is treatable by reducing the activity (partially or fully) of α

4β

7 in the subject.

31. The method of claim 30, wherein the subject is a human being.

32. The method of claim 30, wherein the condition is an inflammatory condition of the gastrointestinal system.

36. The method of claim 32, 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.

40. The method of claim 36, wherein when the 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 dimer molecule comprises a pharmaceutical preparation that is administered orally.

41. The method of claim 36, wherein when the half-life is from approximately 12 hours to greater than 24 in vivo, the α

4β

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

42. The method of claim 36, wherein when the half-life is from approximately 12 hours to greater than 24 hours in vivo, the α

4β

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

33. 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 dimer of Formula (I) in an amount sufficient to inhibit (partially or fully) the biological function of α

4β

7 to tissues expressing MAdCAM.

35. The method of claim 33, wherein the condition is inflammatory bowel disease.

37. The method of claim 33, wherein the peptide dimer 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.

39. The method of claim 37, wherein the increased half-life is at least one day in vitro or in vivo.

34. 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 dimer of Formula (I) in an effective amount sufficient to at least partially inhibit the biological function of α

4β

7 to tissues expressing MAdCAM.

38. A method for treating an individual with an α

4β

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

4β

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