NOVEL a4ß7 PEPTIDE DIMER ANTAGONISTS

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 α4β7 binding.

What is claimed is: 
     
         1 . A peptide dimer compound comprising two peptide monomer subunits of Formula (I)
   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 -Xaa 15    (I),
   
       or a pharmaceutically acceptable salt thereof, wherein
 Xaa 1  is selected from the group consisting of a suitable linker moiety, absent, hydrogen, Ac-, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a corresponding D-amino acid, and a suitable linker moiety; 
 Xaa 2  is selected from the group consisting of Ac-, NH 2 , a suitable linker moiety, absent, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid; 
 Xaa 3  is selected from the group consisting of Ac-, NH 2 , a suitable linker moiety, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid; 
 Xaa 4  is selected from the group consisting of Cys, Pen, Asp, Glu, hGlu, Lys, homo-Lys, Orn, Dap, Dab, a suitable isostere, and a corresponding D-amino acid; 
 Xaa 5  is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, homo-Arg, Dap, Dab, N-Me-Arg, Arg-(Me)sym, Arg-(me)asym, 4-Guan, Cit, Cav, a suitable isostere, and a corresponding D-amino acid; 
 Xaa 6  is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, a suitable isostere replacement and a corresponding D-amino acid; 
 Xaa 7  is selected from the group consisting of Asp, N-Me-Asp, a suitable isostere replacement for Asp, and a corresponding D-amino acid; 
 Xaa 8  is selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tye, Trp, Met, an N-Methyl amino acid; a suitable isostere, and a corresponding D-amino acid; 
 Xaa 9  is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Asn, Glu, Val, homo-Leu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, N-Me-Leu, a suitable isostere, and a corresponding D-amino acid; 
 Xaa 10  is selected from the group consisting of Cys, Asp, Pen, Lys, homo-Lys, Orn, GluDap, Dab, a suitable isostere, and a corresponding D-amino acid; 
 Xaa 11  is selected from the group consisting of Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, CONH 2 , His, Glu, Ser, Arg, Pro, Phe, Sar, 1Nal, 2Nal, hPhe, 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, 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. 
 Xaa 12  is selected from the group consisting of Glu, Amide, Lys, COOH, CONH 2 , Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, a suitable isostere, a suitable linker moiety, and a corresponding D-amino acid; 
 Xaa 13  is selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, COOH, CONH 2 , NH 2 , absent, a suitable linker moiety, a suitable isostere, and a corresponding D-amino acid; 
 Xaa 14  is selected from the group consisting of a natural amino acid, absent, COOH, CONH 2 , NH 2 , a suitable isostere, a suitable linker, a corresponding D-amino acid, and an N-Methyl amino acid; and 
 Xaa 15  is selected from the group consisting of a suitable linker, and absent. 
 
     
     
         2 - 7 . (canceled) 
     
     
         8 . A method for treating inflammatory bowel disease in a patient, comprising administering to the patient an effective amount of a peptide dimer compound of  claim 1 . 
     
     
         9 - 11 . (canceled) 
     
     
         12 . A method for treating a human having an inflammatory bowel disease, comprising the steps of administering to the human an effective amount of a peptide dimer according to the composition of  claim 1 . 
     
     
         13 - 19 . (canceled) 
     
     
         20 . A method for treating a human afflicted with a condition that is associated with a biological function of α4β7, the method comprising administering to the human a peptide dimer according to the composition of  claim 1 . 
     
     
         21 - 22 . (canceled) 
     
     
         23 . A method for stabilizing a peptide dimer compound according to  claim 1 , the method comprising a step for substituting Xaa 4  and Xaa 10  with an amino acid residue selected from the group consisting of Cys and Pen, wherein Xaa 4  and Xaa 10  form a cyclized structure through a disulfide bond. 
     
     
         24 . A method for stabilizing a peptide dimer compound of Formula (II)
   Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Xaa 11 -Xaa 12    (II),
   
       or a pharmaceutically acceptable salt thereof, wherein the method comprises a step for substituting Xaa 4  and Xaa 10  with compatible amino acid residues that are capable of forming a cyclized structure through at least one of an amide bond and a disulfide bond. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . A pharmaceutical composition comprising a peptide dimer compound according to at least one of Formula (I) and Formula (II). 
     
     
         28 - 29 . (canceled) 
     
     
         30 . A method for treating a condition in a subject comprising administering the pharmaceutical composition of  claim 27  to the subject, wherein the condition is treatable by reducing the activity (partially or fully) of α4β7 in the subject. 
     
     
         31 - 22 . (canceled) 
     
     
         33 . A method for treating a human afflicted with a condition that is associated with a biological function α4β7 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 α4β7 to tissues expressing MAdCAM. 
     
     
         34 - 42 . (canceled)