α4β7 thioether peptide dimer antagonists

• US 10,059,744 B2
• Filed: 06/05/2017
• Issued: 08/28/2018
• 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.
• Primary Examiner(s): Reynolds, Fred H
• Application Number:
  US15/614,047
• Publication Number:
  US 20180099995A1
• Time in Patent Office: 449 Days
• Field of Search: None
• 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. A peptide comprising the sequence:

2. The peptide of claim 1, comprising a thioether bond between the 2-methylbenzoyl and the Pen.

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, comprising a C-terminal OH.

7. The peptide of claim 1, comprising a C-terminal NH₂.

8. The peptide of claim 1, comprising a thioether bond between the 2-methylbenzoyl and the Pen, and a linker moiety bound to the D-Lys amino acid.

9. A peptide dimer compound comprising two peptides, each peptide comprising the sequence:

10. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein the linker moiety is bound to the D-Lys amino acids of the two peptides.

11. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein the linker moiety is diglycolic acid (DIG).

12. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen.

13. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides comprises a C-terminal NH₂.

14. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides comprises a C-terminal OH.

15. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, and wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides.

16. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides consists of the sequence:

17. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, wherein each of the two peptides consists of the sequence:

18. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 9, 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 or pharmaceutically acceptable salt thereof of claim 9, and a pharmaceutically acceptable excipient, carrier or diluent.

20. The pharmaceutical composition of claim 19, wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).

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 19, wherein each of the two peptides consists of the sequence:

23. The pharmaceutical composition of claim 19, wherein each of the two peptides consists of the sequence:

24. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises an enteric coating.

25. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is formulated for oral delivery.

26. The pharmaceutical composition of claim 25, further comprising an enteric coating.

27. The pharmaceutical composition of claim 26, wherein the enteric coating releases the pharmaceutical composition within a subject'"'"'s lower gastrointestinal system.

28. A method for treating an Inflammatory Bowel Disease (IBD) in a subject, the method comprising providing to the subject an effective amount of the pharmaceutical composition of claim 19.

29. The method of claim 28, wherein the IBD is ulcerative colitis.

30. The method of claim 28, wherein the IBD is Crohn'"'"'s disease.

31. The method of claim 28, wherein the peptide molecule is administered orally.