α4β7 peptide monomer and dimer antagonists

• US 9,809,623 B2
• Filed: 10/01/2015
• Issued: 11/07/2017
• 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
• Primary Examiner(s): Ahmed, Hasan
• Assistant Examiner(s): DABKOWSKI, ERINNE R
• Application Number:
  US14/872,975
• Publication Number:
  US 20160152664A1
• Time in Patent Office: 768 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: 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 method for treating an inflammatory bowel disease in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a peptide dimer compound comprising two monomer subunits, wherein each monomer subunit comprises the amino acid sequence:

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

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

or a pharmaceutically acceptable salt thereof,

and wherein the two monomer subunits are linked by a linker moiety.

2. The method of claim 1, wherein the inflammatory bowel disease is ulcerative colitis.

3. The method of claim 1, wherein the pharmaceutical composition is administered orally.

4. The method of claim 1, wherein the linker moiety is bound to the D-Lys amino acids of the two monomer subunits.

5. The method of claim 1, wherein the linker moiety is diglycolic acid (DIG).

6. The method of claim 1, wherein each of the two monomer subunits comprises a disulfide bond between the two Pen amino acids.

7. The method of claim 1, wherein the N-terminus of each of the two monomer subunits is acylated.

8. The method of claim 1, wherein each of the two monomer subunits comprises a C-terminal free amide.

9. The method of claim 1, where each of the two monomer subunits comprises a disulfide bond between the two Pen amino acids and wherein the N-terminus of each of the two peptides is acylated.

10. The method of claim 1, wherein the peptide dimer compound or pharmaceutically acceptable salt thereof comprises the structure:

11. The method of claim 1, wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.

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

13. The method of claim 1, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

14. The method of claim 1, wherein the inflammatory bowel disease is microscopic colitis.