NOVEL A4B7 PEPTIDE DIMER ANTAGONISTS
First Claim
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1. A peptide dimer compound comprising two peptide monomer subunits of Formula (I)Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14, or a pharmaceutically acceptable salt thereof, whereinXaa1 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid;
- Xaa2 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid;
Xaa3 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Met, Thr, Ser, a suitable isostere, and a corresponding D-amino acid;
Xaa4 is selected from the group consisting of Cys, Asp, Glu, Lys, Pen, HGlu, HLys, Orn, Dap, Dab, β
Asp, β
Glu, HGlu, HLys, a suitable isostere, and a corresponding D-amino acid;
Xaa5 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Tyr, Trp, Met, Thr, hArg, 4-Guan, Phe(4-NH2), Cit, Cav, Dap, Dab, a suitable isostere, and a corresponding D-amino acid;
Xaa6 is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Thr, Trp, Tyr, Met, a suitable isostere replacement and a corresponding D-amino acid;
Xaa7 is selected from the group consisting of Asp, and a suitable isostere replacement;
Xaa8 is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Val, Tyr, Trp, Leu, Met, a suitable isostere, and a corresponding D-amino acid;
Xaa9 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, HCha, a suitable isostere, and a corresponding D-amino acid;
Xaa10 is selected from the group consisting of Cys, Asp, Lys, Glu, Pen, HAsp, HGlu, HLys, Orn, Dap, Dab, HLys, a suitable isostere, and a corresponding D-amino acid;
Xaa11 is selected from the group consisting of absent, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Ser, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, HPhe, Phe(4-F), dihydro-Trp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, Bip, Ala(3,3 diphenyl), Biphenyl-Ala, D-Phe, D-Trp, D-Tyr, D-Glu, D-His, D-Lys, 3,3-diPhe, β
-HTrp, F(4-CF3), O-Me-Tyr, 4-Me-Phe, an aromatic ring substituted Phe, an aromatic ring substituted Trp, an aromatic ring substituted His, a hetero aromatic amino acid, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, a corresponding D-amino acid;
a suitable isostere; and
a suitable linker moiety.Xaa12 is selected from the group consisting of absent, Glu, Lys, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, Asp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, β
-HGlu, 2-Nal, 1-Nal, Bip, β
-HPhe, β
Glu, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;
Xaa13 is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, absent, a suitable isostere, and a corresponding D-amino acid; and
Xaa14 is selected from the group consisting of absent, a natural amino acid, a suitable isostere, and a corresponding D-amino acid,wherein the peptide dimer compound further comprises at least one of a disulfide bond and a lactam bond between Xaa4 and Xaa10.
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Abstract
The invention relates to disulfide-rich dimer molecules which inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, and show high selectivity against α4β1 binding.
27 Citations
50 Claims
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1. A peptide dimer compound comprising two peptide monomer subunits of Formula (I)
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14, or a pharmaceutically acceptable salt thereof, wherein Xaa1 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid; -
Xaa2 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Ser, Met, Thr, a suitable isostere, and a corresponding D-amino acid; Xaa3 is selected from the group consisting of absent, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Met, Thr, Ser, a suitable isostere, and a corresponding D-amino acid; Xaa4 is selected from the group consisting of Cys, Asp, Glu, Lys, Pen, HGlu, HLys, Orn, Dap, Dab, β
Asp, β
Glu, HGlu, HLys, a suitable isostere, and a corresponding D-amino acid;Xaa5 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Tyr, Trp, Met, Thr, hArg, 4-Guan, Phe(4-NH2), Cit, Cav, Dap, Dab, a suitable isostere, and a corresponding D-amino acid; Xaa6 is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Thr, Trp, Tyr, Met, a suitable isostere replacement and a corresponding D-amino acid; Xaa7 is selected from the group consisting of Asp, and a suitable isostere replacement; Xaa8 is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Val, Tyr, Trp, Leu, Met, a suitable isostere, and a corresponding D-amino acid; Xaa9 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, HCha, a suitable isostere, and a corresponding D-amino acid; Xaa10 is selected from the group consisting of Cys, Asp, Lys, Glu, Pen, HAsp, HGlu, HLys, Orn, Dap, Dab, HLys, a suitable isostere, and a corresponding D-amino acid; Xaa11 is selected from the group consisting of absent, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Ser, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, HPhe, Phe(4-F), dihydro-Trp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, Bip, Ala(3,3 diphenyl), Biphenyl-Ala, D-Phe, D-Trp, D-Tyr, D-Glu, D-His, D-Lys, 3,3-diPhe, β
-HTrp, F(4-CF3), O-Me-Tyr, 4-Me-Phe, an aromatic ring substituted Phe, an aromatic ring substituted Trp, an aromatic ring substituted His, a hetero aromatic amino acid, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, a corresponding D-amino acid;
a suitable isostere; and
a suitable linker moiety.Xaa12 is selected from the group consisting of absent, Glu, Lys, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, Asp, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, β
-HGlu, 2-Nal, 1-Nal, Bip, β
-HPhe, β
Glu, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid;Xaa13 is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, D-Dap, D-Dab, absent, a suitable isostere, and a corresponding D-amino acid; and Xaa14 is selected from the group consisting of absent, a natural amino acid, a suitable isostere, and a corresponding D-amino acid, wherein the peptide dimer compound further comprises at least one of a disulfide bond and a lactam bond between Xaa4 and Xaa10. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)
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28. A method for stabilizing a peptide dimer compound of Formula (II)
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10, or a pharmaceutically acceptable salt thereof, wherein the method comprises a step for substituting Xaa1 and Xaa7 with compatible amino acid residues that are capable of forming a cyclized structure through at least one of disulfide bond or lactam bond.
- 31. A pharmaceutical composition comprising a peptide dimer compound according to at least one of Formula (I) and Formula (II).
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37. A method for treating a human afflicted with a condition that is associated with a biological function α
- 4β
7 and comprising administering to the individual a peptide dimer of Formula (I) in an amount sufficient to inhibit (partially or fully) the biological function of α
4β
7 to tissues expressing MAdCAM. - View Dependent Claims (39, 40, 41)
- 4β
-
38. A method for treating a human afflicted with a condition that is associated with a biological function of α
- 4β
7 and comprising administering to the individual a peptide dimer of Formula (I) in an effective amount sufficient to at least partially inhibit the biological function of α
4β
7 to tissues expressing MAdCAM.
- 4β
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42. A method for treating an individual with an α
- 4β
7 integrin antagonist dimer molecule according to at least one of Formula (I) and Formula (II), wherein the α
4β
7 integrin antagonist dimer molecule comprises an increased half-life. - View Dependent Claims (43, 44, 45, 46)
- 4β
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47. A method for increasing SIF stability of peptide dimer molecule according to SEQ ID NOs:
- 1-146, comprising a step for substituting N-Me-Arg for one or more unmethylated arginine residues.
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48. A method for increasing SIF stability of a peptide dimer molecule according to SEQ ID NOs:
- 1-146, comprising a step for substituting Pen for one or more cysteine residues.
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49. A method for increasing redox stability of a peptide dimer molecule according to SEQ ID NOs:
- 1-146, comprising a step for substituting Pen for one or more cysteine residues.
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50. A method for increasing potency of a peptide molecule for α
- 4b7 according to SEQ ID NOs;
1-146, comprising forming a dimer molecule through a C- or N-terminal dimerization.
- 4b7 according to SEQ ID NOs;
Specification