NOVEL a4B7 PEPTIDE MONOMER AND DIMER ANTAGONISTS

• US 20180148477A1
• Filed: 09/07/2017
• Published: 05/31/2018
• Est. Priority Date: 10/01/2014
• Status: Abandoned Application

• Current Assignee: Protagonist Therapeutics, Inc.
• Original Assignee: Protagonist Therapeutics, Inc.
• Inventors: Bhandari, Ashok, Patel, Dinesh V., Zemede, Genet, Mattheakis, Larry C., Liu, David
• Application Number:
  US15/698,407
• Publication Number:
  US 20180148477A1
• Time in Patent Office: 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 peptide dimer compound comprising two linked monomer subunits of Formula (I):

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

 

(Formula (I))

or a pharmaceutically acceptable salt thereof,

wherein;

Xaa¹ is absent, Ac, or any amino acid;

Xaa² is absent, Ac, or any amino acid;

Xaa³ is absent, Ac, or any amino acid;

Xaa⁴ is Pen or Cys;

Xaa⁵ is selected from the group consisting of;

N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidinoguanidino), Phe(4-carbomyl), Cit, Phe(4-NH₂), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;

Xaa⁶ is Ser, Ile, Gly, Thr or Ile;

Xaa⁷ is Asp, Asp(OMe) or N-Me-Asp;

Xaa⁸ is selected from the group consisting of;

Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;

Xaa⁹ is selected from the group consisting of;

Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, cyclopentylAla, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen;

Xaa¹¹ is absent or selected from the group consisting of;

aromatic amino acids, substituted aromatic amino acids, and Tic;

Xaa¹² is absent or selected from the group consisting of;

aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gin, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, Homo-Phe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;

Xaa¹³ is absent or Pro or any amino acid; and

Xaa¹⁴ is selected from the group consisting of;

any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, HomoGlu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp;

wherein one or both monomer subunits of the peptide dimer compound comprises a disulfide bond between Xaa⁴ and Xaa¹⁰.

2. The peptide dimer compound of claim 1, further comprising a linker moiety linking the two monomer subunits, wherein the linker moiety is optionally selected from the group consisting of DIG, PEG13, PEG25, PEG1K, PEG2, 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, cyclopropylacetic acid, 4-fluoorobenzoic acid, 4-fluorophenylacetic acid, 3-phenylpropionic acid, succinic acid, biotin, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, aliphatic amino acids, aromatic amino acids, heteroaromatics, polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da, bifunctional linkers, N-Hydroxy succinamine (NHS)-activated diesters, and bis-maleimides.

3. The peptide dimer compound of claim 2, wherein the N-terminus of each monomer subunit is linked by the linker moiety to provide an N-terminus dimer compound.

4. The peptide dimer compound of claim 2, wherein the C-terminus of each monomer subunit is joined by the linker moiety to provide a C-terminus dimer compound.

5. The peptide dimer compound of claim 1, wherein

Xaa⁵ is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-homoArg;

Xaa⁸ is selected from the group consisting of Leu, homoLeu, Nle and Val;

Xaa⁹ is selected from the group consisting of Cba, homoLeu, and Cpa;

Xaa¹¹ is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu);

Xaa¹² is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val;

or

Xaa¹³ is Pro.

6. The peptide dimer compound of claim 1, wherein Xaa⁵ is N-Me-Arg, Xaa⁶ is Ser, Xaa⁷ is Asp, Xaa⁸ is Thr, and/or Xaa⁹ is Leu.

7. The peptide dimer compound of claim 1, wherein Xaa^1l is Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), or Phe(4-tBu).

8. The peptide dimer compound of claim 1, wherein:

Xaa⁵ is N-Methyl-Arg;

Xaa⁶ is Ser;

Xaa⁷ is Asp;

Xaa⁸ is Thr or Val;

Xaa⁹ is Leu;

Xaa¹¹ is selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF₃), Phe(4-CH₃), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3 diPhenyl Ala, Tic, β

-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), and HomoPhe;

Xaa¹² is selected from the group consisting of;

any aromatic amino acid, Glu, D-Glu, and beta-homoGlu;

Xaa¹³ is absent; and

Xaa¹⁴ is selected from the group consisting of;

D-Lys, N-Me-Lys, and D-N-Me-Lys.

9. The peptide dimer compound of claim 8, wherein both subunits comprise one of the following sequences:

11. The peptide dimer compound of claim 9, where the subunits are linked via a DIG linker.

12. The peptide dimer compound of claim 9, wherein the peptide dimer compound has one of the following structures:

16. The peptide dimer compound of claim 1, further comprising acylation at one or more position selected from the group consisting of Xaa¹-Xaa³ and Xaa¹¹-Xaa¹⁴.

17. The peptide dimer compound of claim 1, wherein Xaa¹ and Xaa² are absent, and Xaa³ is Ac;

and one or more of Xaa¹¹, Xaa¹² and Xaa¹³ is absent.

23. The peptide monomer compound of claim 1, wherein the peptide monomer compound comprises one of the following sequences or structures:

24. A compound of claim 1, wherein the compound is detectably labeled.

25. A pharmaceutical composition comprising a compound of claim 1.

26. The composition of claim 24, further comprising an enteric coating, wherein the enteric coating protects and releases the pharmaceutical composition within a subject'"'"'s lower gastrointestinal system

27. A method for treating a subject afflicted with a condition that is associated with a biological function of an α

4β

7 integrin, the method comprising administering to the human an effective amount of a compound of claim 1.

10. (canceled)

13-15. -15. (canceled)

18. (canceled)

19. A peptide monomer compound of Formula (IV):

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

 

(Formula (IV))

or a pharmaceutically acceptable salt thereof,

wherein;

Xaa¹ is absent, Ac, or any amino acid;

Xaa² is absent, Ac, or any amino acid;

Xaa³ is absent, Ac, or any amino acid;

Xaa⁴ is Pen and Cys;

Xaa⁵ is selected from the group consisting of;

N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidino), Phe(4-carbomylamino), Cit, Phe(4-NH₂), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;

Xaa⁶ is Ser Gly, Thr, or Ile;

Xaa⁷ is Asp, Asp(OMe), or N-Me-Asp;

Xaa⁸ is selected from the group consisting of;

Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;

Xaa⁹ is selected from the group consisting of;

Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, cyclopentylAla, Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

Xaa¹⁰ is Pen;

Xaa¹¹ is absent or selected from the group consisting of;

Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF₃), Phe(4-CH₃), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, aromatic amino acids, substituted aromatic amino acids, and Tic;

Xaa¹² is absent or selected from the group consisting of;

aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, Homo-Phe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;

Xaa¹³ is absent or Pro or any amino acid; and

Xaa¹⁴ is any amino acid,

wherein the peptide monomer compound comprises a disulfide bond between Xaa⁴ and Xaa¹⁰.

22. The peptide monomer compound of claim 19, wherein Xaa¹ and Xaa² are absent, and Xaa³ is Ac, Xaa⁵ is N-Me-Arg, and/or wherein one or more of Xaa¹¹, Xaa¹² and Xaa¹³ is absent.

20. A peptide monomer compound of Formula (V):

Xaa¹-Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷-Xaa⁸-Xaa⁹-Xaa¹⁰ 

 

(Formula (V))

or a pharmaceutically acceptable salt thereof,

wherein the peptide compound comprises a disulfide bond Xaa¹ and Xaa⁷;

wherein Xaa¹-Xaa¹⁰ of Formula (V) corresponds to Xaa⁴-Xaa¹³ of Formula (IV), and

wherein

Xaa¹ is Pen;

Xaa² is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-HomoArg;

Xaa³ is Ser Gly, Thr, or Ile;

Xaa⁴ is Asp, D-Asp, Asp(OMe), or N-Me-Asp;

Xaa⁵ is selected from the group consisting of Leu, HomoLeu, Nle and Val;

Xaa⁶ is selected from the group consisting of;

Cba, HomoLeu, and Cpa;

Xaa⁷ is Pen;

Xaa⁸ is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu);

Xaa⁹ is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; and

Xaa¹⁰ is Pro.

21. (canceled)

28-41. -41. (canceled)