NOVEL CYCLIC MONOMER AND DIMER PEPTIDES HAVING INTEGRIN ANTAGONIST ACTIVITY
First Claim
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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.
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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.
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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