NOVEL a4B7 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 α4β1 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 . The peptide dimer compound of  claim 1 , wherein when Xaa 1  is absent, Xaa 2  is selected from the group consisting of Ac, NH 2  and a suitable linker. 
     
     
         3 . The peptide dimer compound of  claim 1 , wherein when Xaa 1  and Xaa 2  are absent, Xaa 3  is selected from the group consisting of Ac, NH 2  and a suitable linker. 
     
     
         4 . The peptide dimer compound of  claim 1 , wherein when Xaa 10  is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, Xaa 4  is selected from the group consisting of Asp, Glu, and hGlu, and when Xaa 10  is selected from the group consisting of Asp, Glu, and hGlu, Xaa 4  is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab. 
     
     
         5 . The peptide dimer compound of  claim 1 , wherein when Xaa 4  and Xaa 10  are selected from the group consisting of Cys and Pen, Xaa 4  and Xaa 10  are cyclized through a disulfide bond. 
     
     
         6 . The peptide dimer compound of  claim 1 , wherein when Xaa 4  is selected from the group consisting of Lys, homo-Lys, Orn, Dap, and Dab, and when Xaa 10  is selected from the group consisting of Asp, Glu, and hGlu, Xaa 4  and Xaa 10  are cyclized through an amide bond. 
     
     
         7 . The peptide dimer compound of  claim 1 , wherein the suitable linker is selected from the group consisting of DIG, DIG-OH, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, suitable aromatics, heteroaromatics, and polyethylene glycols having a molecular weight from approximately 400 Da to approximately 40,000 Da. 
     
     
         8 . A method for treating a patient afflicted with a condition that is associated with a biological function of α4β7, the method comprising administering to the patient an effective amount of a peptide dimer compound of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein the condition is an inflammatory bowel disease. 
     
     
         10 . The method of  claim 9 , wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. 
     
     
         11 . (canceled) 
     
     
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         18 . The method of  claim 8 , wherein the peptide dimer is selected from the group consisting of SEQ ID NO: 39-136. 
     
     
         19 . (canceled) 
     
     
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         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 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . A pharmaceutical composition comprising a peptide dimer compound according to at least one of Formula (I) and Formula (II). 
     
     
         28 . The composition of  claim 27 , further comprising an enteric coating. 
     
     
         29 . (canceled) 
     
     
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         31 . (canceled) 
     
     
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         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . The method of  claim 8 , wherein the condition is selected from the group consisting of Inflammatory Bowel Disease (IBD), ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiotherapy, chemotherapy, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, and graft versus host disease. 
     
     
         37 . The method of  claim 8 , wherein the peptide dimer is administered to the individual by a form of administration selected from the group consisting of oral, intravenous, peritoneal, intradermal, subcutaneous, intramuscular, intrathecal, inhalation, vaporization, nebulization, sublingual, buccal, parenteral, rectal, vaginal, and topical. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled)