a4B7 integrin thioether peptide antagonists

Patent metadata

Field	Value
Publication number	US-9714270-B2
Application number	US-201514714198-A
Country	US
Kind code	B2
Filing date	May 15, 2015
Priority date	May 16, 2014
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

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.

First claim

The invention claimed is:

1. A peptide molecule comprising a structure of Formula (V) (SEQ ID NO: 49):

(Formula (V)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -

Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14

or a pharmaceutically acceptable salt thereof, wherein the peptide comprises a thioether bond between Xaa 4 and Xaa 10 , and wherein:
Xaa 1 is absent or any amino acid;
Xaa 2 is absent or any amino acid;
Xaa 3 is absent or any amino acid;
Xaa 4 is a methyl benzoyl moiety capable of forming a thioether bond with Xaa 10 ;
Xaa 5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, HomoArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, 4-Guan, Cit, Cav, N-Me-Lys, Phe(4-quanidino), Phe(4-carbamoyl amino), Phe(4-NH 2 ), N-Me-HomoArg, Tyr, His, and suitable isostere replacements;
Xaa 6 is selected from the group consisting of Ser, Gly, Thr, Ile, and suitable isostere replacements;
Xaa 7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and suitable isostere replacements;
Xaa 8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, HomoLeu, Nle, and N-Methyl amino acids including N-Me-Thr;
Xaa 9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, Cpa, Cba, Aoc, N-Me-Leu, and suitable isostere replacements;
Xaa 10 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, D-Pen, and Pen(=O);
Xaa 11 is absent or 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, b-homo-Trp, 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, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, D-1-Nal, D-2-Nal, HPhe, D-Phe, D-Tyr, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, Phe(4-OMe), Phe(CF3), Aic, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β-Me-Phe, and corresponding D-amino acids and suitable isostere replacements;
Xaa 12 is absent or selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, HomoGlu, Beta-Homo-Glu, Asp, D-HomoGlu, Amide, Lys, COOH, CONH 2 , Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, β-HGlu, 2-Nal, 1-Nal, D-Asp, Bip, β-HPhe, β-Glu, D-Tyr, D-Phe, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, D-His, F(4-COOH), Tic, D-Trp, D-Leu, D-Arg, D-Thr, N-Me-Glu, N-Me-Asp, alpha-H-Glu, isosteres, and corresponding D-amino acids;
Xaa 13 is absent or any amino acid; and
Xaa 14 is absent or any amino acid;
wherein if the peptide molecule is a peptide dimer or subunit thereof, then Xaa 14 is absent or 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, N-Me-Orn, Dab, N-Me-Dab, Dap, N-Me-Dap, Homo-Lys, D-Dap, D-Dab, D-Orn, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Cys, HomoCys, COOH, CONH 2 , suitable isosteres, corresponding D-amino acids, and corresponding N-Methyl amino acids, and
wherein the peptide molecule comprises a thioether bond between Xaa 4 and Xaa 10 .

2. The peptide molecule of claim 1 , wherein
Xaa 1 is absent or any amino acid;
Xaa 2 is absent or any amino acid;
Xaa 3 is absent or any amino acid;
Xaa 4 is a 2-methyl-benzoyl moiety capable of forming a thioether bond with Xaa 10 ;
Xaa 5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe (4-quanidino), Phe(4-carbamoyl amino), Cit, Phe(4-NH2), N-Me-Homo-Arg, Homo-Arg, Tyr and His;
Xaa 6 is Ser, Gly, Thr or Ile;
Xaa 7 is Asp or D-Asp;
Xaa 8 is selected from the group consisting of: Thr, Val, Ile, Leu, hLeu, Nle, and Val;
Xaa 9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;
Xaa 10 is Pen, Cys, D-Cys or HomoCys; and
Xaa 11 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-homo-Trp, 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, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β-Me-Phe, and Ser;
Xaa 12 is absent or selected from the group consisting of: any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-homoGlu, D-Asp, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid, and isosteres;
Xaa 13 is absent or any amino acid; and
Xaa 14 is any amino acid.

3. The peptide molecule of claim 1 , wherein
Xaa 1 is absent or any amino acid;
Xaa 2 is absent or any amino acid;
Xaa 3 is absent or any amino acid;
Xaa 4 is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa 10 ;
Xaa 5 is N-Me-Arg;
Xaa 6 is Ser, Gly, Thr, or Ile;
Xaa 7 is Asp or D-Asp;
Xaa 8 is selected from the group consisting of: Thr, Val, Ile, Leu, hLeu and Nle;
Xaa 9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;
Xaa 10 is Pen, Cys, D-Cys or HomoCys;
Xaa 11 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, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), HomoPhe, N-Me-Phe, N-Me-Tyr, Dihydro Trp, Ile, Leu, Ser, Arg, Thr, Sar, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β-Me-Phe, and any substituted aromatic amino acid and corresponding D-amino acids;
Xaa 12 is selected from the group consisting of: any aromatic amino acid, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homo-Glu, N-Me-Glu, N-Me-Asp, alpha-H-Glu, corresponding D-amino acid and isosteres;
Xaa 13 is absent; and
Xaa 14 is any amino acid.

4. The peptide molecule of claim 1 , wherein
Xaa 1 is absent or any amino acid;
Xaa 2 is absent or any amino acid;
Xaa 3 is absent or any amino acid;
Xaa 4 is a 2-methylbenzoyl moiety capable of forming a thioether bond with Xaa 10 ;
Xaa 5 is N-Me-Arg;
Xaa 6 is Ser, Gly, Thr, or Ile;
Xaa 7 is Asp or D-Asp;
Xaa 8 is selected from the group consisting of: Thr, Val, Ile, Leu, hLeu and Nle;
Xaa 9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, HomoLeu, Aoc, and N-Me-Leu;
Xaa 10 is Pen, Cys, D-Cys or HomoCys;
Xaa 11 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, b-homo-Trp, D-1-Nal, D-2-Nal, Phe(2,4-di

Assignees

• Protagonist Therapeutics Inc

Inventors

• Bhandari Ashok
• Patel Dinesh V
• Zemede Genet
• Frederick Brian Troy
• Mattheakis Larry C

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title