NOVEL a4B7 PEPTIDE MONOMER AND DIMER ANTAGONISTS
First Claim
Patent Images
1. A peptide dimer compound comprising two linked monomer subunits of Formula (I):
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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, 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 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;
Xaa5 is selected from the group consisting of Cit, Phe(4-carbomylamino), 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;
orXaa13 is Pro;
wherein one or both monomer subunits of the peptide dimer compound comprises a disulfide bond between Xaa4 and Xaa10, andwherein the peptide dimer compound comprises a linker moiety linking the two monomer subunits.
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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.
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Citations
36 Claims
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1. A peptide dimer compound comprising two linked monomer subunits of Formula (I):
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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, 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 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; Xaa5 is selected from the group consisting of Cit, Phe(4-carbomylamino), 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;
orXaa13 is Pro; wherein one or both monomer subunits of the peptide dimer compound comprises a disulfide bond between Xaa4 and Xaa10, and wherein the peptide dimer compound comprises a linker moiety linking the two monomer subunits. - View Dependent Claims (2, 3, 4, 5, 6, 7, 14, 17, 24, 25, 26, 27, 28, 29, 30, 35)
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8. The peptide dimer compound of wherein:
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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. - View Dependent Claims (9, 11, 13)
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10. (canceled)
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12. (canceled)
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15-16. -16. (canceled)
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18. (canceled)
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19. A peptide monomer compound of Formula (IV):
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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 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;
orXaa13 is Pro; and wherein the peptide monomer compound comprises a disulfide bond between Xaa4 and Xaa10. - View Dependent Claims (22, 23)
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20-21. -21. (canceled)
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31-34. -34. (canceled)
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36-41. -41. (canceled)
Specification