α4β7 peptide dimer antagonists

• US 9,273,093 B2
• Filed: 10/10/2013
• Issued: 03/01/2016
• Est. Priority Date: 10/11/2012
• Status: Active Grant

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Mattheakis, Larry C.
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): DABKOWSKI, ERINNE R
• Application Number:
  US14/050,349
• Publication Number:
  US 20140193465A1
• Time in Patent Office: 873 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 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 absent;

Xaa² is absent;

Xaa³ is selected from the group consisting of Ac- and NH₂;

Xaa⁴ is selected from the group consisting of Cys and Pen;

Xaa⁵ is N-Me-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp;

Xaa⁸ is Thr;

Xaa⁹ is Leu;

Xaa¹⁰ is selected from the group consisting of Cys and Pen;

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, N-Me-Orn, N-Me-Dap, D-Orn, D-Dap, D-Dab, Bip, Ala(3,3 diphenyl), 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, and corresponding D-amino acids thereof;

Xaa¹² is selected from the group consisting of Glu, Lys COOH, CONH₂, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, 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, absent, a linker moiety, and corresponding D-amino acids thereof;

Xaa¹³ is selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, 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 linker moiety, and corresponding D-amino acids thereof;

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

Xaa¹⁵ is selected from the group consisting of a linker moiety and absent;

wherein Xaa⁴ or Xaa¹⁰ is pen;

wherein Xaa⁴ and Xaa¹⁰ are cyclized via a disulfide bond; and

wherein the two peptide monomer subunits are dimerized at their respective C-termini.

2. The peptide dimer of claim 1, wherein the linker moiety is selected from the group consisting of diglycolic acid (DIG), DIG-OH, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, β

-Ala-Iminodiacetic acid (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, and polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da.

3. A pharmaceutical composition comprising a peptide dimer compound of claim 1.

4. The pharmaceutical composition of claim 3, further comprising an enteric coating.

5. The pharmaceutical composition of claim 4, wherein the enteric coating protects and releases the pharmaceutical composition within a subject'"'"'s lower gastrointestinal system.

6. The peptide dimer of claim 2, wherein the linker moiety is DIG.

7. The peptide dimer of claim 1, wherein Xaa¹⁴ and Xaa¹⁵ are absent, and Xaa¹³ is the linker moiety.

8. The peptide dimer of claim 1, wherein Xaa⁴ and Xaa¹⁰ are Pen.