NOVEL CYCLIC MONOMER AND DIMER PEPTIDES HAVING INTEGRIN ANTAGONIST ACTIVITY
First Claim
Patent Images
1. A cyclic dimer compound comprising two peptide monomer subunits of Formula (VII):
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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, and 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 dinner compound comprises two linker moieties linking the two peptide monomer subunits via their C-termini and N-terrnini.
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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.
19 Citations
46 Claims
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1. A cyclic dimer compound comprising two peptide monomer subunits of Formula (VII):
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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, and 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 dinner compound comprises two linker moieties linking the two peptide monomer subunits via their C-termini and N-terrnini. - View Dependent Claims (2, 3, 4, 5, 6, 7, 10, 11, 12, 20, 31, 45, 46)
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8-9. -9. (canceled)
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13-15. -15. (canceled)
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16. A compound of formula (IV):
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cyclo-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9
(IV),or a pharmaceutically acceptable salt thereof, wherein Xaa1 is selected from the group consisting of absent and free a-mind -amine (NH2); Xaa2 is selected from the group consisting of dAla, dHis, dLys, dPhe, dLeu, dPro, dArg, Ala, and a suitable isostere; Xaa3 is selected from the group consisting of N-Me-Arg and a suitable isostere; Xaa4 is selected from the group consisting of Ser and a suitable isostere; Xaa5 is selected from the group consisting of Asp and a suitable isostere; Xaa6 is selected from the group consisting of Thr and a suitable isostere; Xaa7 is selected from the group consisting of Leu and a suitable isostere; Xaa8 is selected from the group consisting of dAla, dAsp, dGlu, dLeu, dHis, dLys, and a suitable isostere; and Xaa9 is an amino acid, wherein the compound is cyclized by a linkage between the C-terminal amino acid and the N-terminal amino acid. - View Dependent Claims (17, 18, 19, 43, 44)
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21-30. -30. (canceled)
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32-42. -42. (canceled)
Specification