Cyclic monomer and dimer peptides having integrin antagonist activity

• US 10,301,371 B2
• Filed: 10/01/2015
• Issued: 05/28/2019
• 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
• Primary Examiner(s): Lieb, Jeanette M
• Application Number:
  US15/514,983
• Publication Number:
  US 20180105572A1
• Time in Patent Office: 1,335 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 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/70546 Integrin superfamily
• CPC Class Codes: C07K 14/7055 Integrin beta1-subunit-containing molecules, e.g. CD29, CD49
• 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 C to N cyclized (C-N cyclic) monomer and dimer peptide molecules, as well as peptide dimers which are connected by linker moieties at the N terminus and the C terminus of each peptide subunit, 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 cyclic dimer compound comprising two peptide monomer subunits of Formula (VII):

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

 

(Formula (VII))

or a pharmaceutically acceptable salt thereof,

wherein one or both subunits comprises a disulfide bond, a lactam bond, an olefin bond, a triazole bond, a selenoether bond, a thioether bond, an amide bond, or a diselenide bond between Xaa⁴ and Xaa¹⁰, 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 any amino acid capable of forming a bond with Xaa¹⁰;

Xaa⁵ is selected from the group consisting of;

N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidinoguanidino), Phe(4-carbamoyl), 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, D-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-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;

Xaa¹⁰ is any amino acid capable of forming a bond with Xaa⁴;

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, 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, homoPhe, 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 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, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp,

wherein the cyclic dimer compound comprises two linker moieties linking the two peptide monomer subunits via their C-termini and N-termini.

2. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein 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.

3. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein any one of Xaa′

, Xaa² or Xaa³ is selected from 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, HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

4. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the N-terminal amino acid and/or the C-terminal amino acid is selected from 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, HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

5. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the two linker moieties are selected from the group consisting of:

DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, 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, suitable aliphatics, aromatics, heteroaromatics, polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da, and bifunctional linkers selected from the group consisting of di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, and bis-maleimides.

6. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the C terminus of the first monomer subunit is joined to the C-terminus of the second monomer subunit via a first linker moiety, and the N-terminus of the first monomer subunit is joined to the N-terminus of the second monomer subunit via the second linker moiety to provide a cyclic formation.

7. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising a disulfide bond between Xaa⁴ and Xaa¹⁰.

8. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising a thioether bond between Xaa⁴ and Xaa¹⁰.

9. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising N(alpha)methylation at one or more positions selected from the group consisting of Xaa³, Xaa⁵, Xaa⁷-Xaa⁹, and Xaa¹¹-Xaa¹³.

10. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, further comprising acylation at one or more position selected from the group consisting of Xaa¹-Xaa³ and Xaa¹¹-Xaa¹⁴.

11. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1.

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

4β

7, wherein the method comprises administering to the subject the compound or pharmaceutically acceptable salt thereof of claim 1 or the composition of claim 11.

13. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein Xaa⁵ is N-Me-Arg, Xaa⁶ is Ser, Xaa⁷ is Asp, Xaa⁸ is Thr, and Xaa⁹ is Leu.

14. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein each of the monomer subunits comprises one of the following sequences:

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu)-(D-Lys);

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

-homoGlu)-(D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β

-homoGlu)-(D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu)-(D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys);

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

-homoGlu)-(D-Lys);

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

-homoGlu)-(N-Me-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu)-(N-Me-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β

-homoGlu)-(N-Me-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu)-(D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu)-(N-Me-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu)-(D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu);

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

-homo-Glu);

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

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

-homo-Glu);

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

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu;

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(β

-homo-Glu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu);

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

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu;

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

-homoGlu);

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

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(β

-homoGlu);

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(β

-homoGlu);

or

Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;

wherein there is a disulfide bond between the two Pen residues of each subunit.