NOVEL a4B7 PEPTIDE MONOMER AND DIMER ANTAGONISTS

• US 20160159862A1
• Filed: 02/17/2016
• Published: 06/09/2016
• Est. Priority Date: 10/01/2014
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Zemede, Genet, Mattheakis, Larry C., Liu, David
• Granted Patent: US 9,518,091 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• 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 37/02 : Immunomodulators
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/7051 : T-cell receptor (TcR)-CD3 complex
• 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 peptide dimer compounds and peptide monomer compounds that potently inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, possess high selectivity against α4β1 binding, and have high stability under gastrointestinal conditions.

Claims

1. A peptide comprising or consisting of the amino acid sequence:

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β

-homo-Glu)-(D-Lys).

2. The peptide of claim 1, comprising a disulfide bond between the two Pen amino acids.

3. The peptide of claim 1, further comprising a linker moiety.

4. The peptide of claim 3, wherein the linker moiety is bound to the D-Lys amino acid.

5. The peptide of claim 4, wherein the linker moiety is diglycolic acid (DIG).

6. The peptide of claim 1, wherein the N-terminus of the peptide is acylated.

7. The peptide of claim 1, comprising a C-terminal free amide.

8. The peptide of claim 1, comprising a disulfide bond between the two Pen amino acids and a linker moiety bound to the D-Lys amino acid, wherein the N-terminus of the peptide is acylated.

9. The peptide of claim 8, wherein the linker moiety is bound to the epsilon amino group of the D-Lys amino acid.

10. A peptide dimer compound comprising two peptides, each peptide comprising or consisting of the amino acid sequence:

Pen-(N-Me-Arg)-S er-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β

-homo-Glu)-(D-Lys),

or a pharmaceutically acceptable salt thereof,

wherein the D-Lys amino acids of the two peptides are linked by a linker moiety.

11. The peptide dimer compound of claim 10, wherein the linker moiety is bound to the epsilon amino group of the D-Lys amino acids of the two peptides.

12. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, wherein the linker moiety is diglycolic acid (DIG).

13. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, wherein each of the two peptides comprises a disulfide bond between the two Pen amino acids.

14. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, wherein the N-terminus of each of the two peptides is acylated.

15. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, wherein each of the two peptides comprises a C-terminal free amide.

16. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, where each of the two peptides comprises a disulfide bond between the two Pen amino acids and wherein the N-terminus of each of the two peptides is acylated.

17. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, having the structure:

18. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 10, wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.

19. A pharmaceutical composition comprising the peptide dimer compound of claim 10 and a pharmaceutically acceptable excipient, carrier or diluent.

20. The pharmaceutical composition of claim 19, wherein the peptide dimer compound has the structure:

21. The pharmaceutical composition of claim 20, wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.

22. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition comprises an enteric coating.

23. A method for treating an individual afflicted with a disease or condition characterized by inappropriate trafficking of cells expressing α

4β

7 integrin to tissues comprising cells expressing MAdCAM, comprising administering to the individual an effective amount of the pharmaceutical composition of claim 19.

24. The method of claim 23, wherein the peptide dimer compound has the structure:

25. The method of claim 24, wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.

26. The method of claim 23, wherein the disease or 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, colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type 1b, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, 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.

27. The method of claim 26, wherein the disease or condition is an inflammatory bowel disease.

28. The method of claim 27, wherein the inflammatory bowel disease is ulcerative colitis or Crohn'"'"'s disease.

29. The method of claim 23, wherein the pharmaceutical composition is administered orally, buccally, intravenously, parenterally, or intranasally.

30. The method of claim 21, wherein the individual is a human.