NOVEL a4B7 THIOETHER PEPTIDE DIMER ANTAGONISTS

Abstract

The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.

1 - 19 . (canceled) 
     
     
         20 . A peptide molecule comprising a structure of Formula (VI): 
       
         
           
                 
               
                   (Formula VI) 
                 
                   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 - 
                 
                   Xaa 11   
                 
             
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Xaa 1  is a 2-Me-benzoyl group capable of forming a thioether bond with Xaa 7 ; 
         Xaa 2  is selected from the group consisting of N(alpha)-Me-Arg, Arg, HArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, 4-Guan, Cit, Cav, and suitable isostere replacements; 
         Xaa 3  is selected from the group consisting of Ser, Gly, and suitable isostere replacements; 
         Xaa 4  is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements; 
         Xaa 5  is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr, and suitable isostere replacements; 
         Xaa 6  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, N-Me-Leu, and suitable isostere replacements; 
         Xaa 7  is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, and D-Pen; 
         Xaa 8  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), 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, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), β-Me-Phe, 4-Me-Phe, and corresponding D-amino acids and suitable isostere replacements; 
         Xaa 9  is selected from the group consisting of absent, Glu, Amide, Lys, COOH, CONH 2 , Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, β-HGlu, 2-Nal, 1-Nal, D-Asp, Bip, β-HPhe, β-Glu, D-Tyr, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, Glu, N-Me-Asp, alpha-H-Glu, suitable isosteres, and corresponding D-amino acids; 
         Xaa 10  is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH 2 , suitable isosteres, and corresponding D-amino acids; and 
         Xaa 11  is selected from the group consisting of absent, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH 2 , suitable isosteres, and corresponding D-amino acids, wherein the peptide further comprises a thioether bond between Xaa 1  and Xaa 7 . 
       
     
     
         21 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 20 , wherein Xaa 4  is a 2-methyl benzoyl moiety that forms a thioether bond with Xaa 10 , Xaa 5  is N-Me-Arg, Xaa 6  is Ser, Xaa 7  is Asp, Xaa 8  is Thr, Xaa 9  is Leu, and Xaa 10  is Pen, Cys, D-Cys or HomoCys. 
     
     
         22 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 21 , wherein Xaa 10  is Pen or Cys. 
     
     
         23 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 20 , further comprising a terminal modifying group selected from the group consisting of DIG, PEG4, PEG13, PEG25, PEG1K, PEG2K, PEG4K, PEG5K, Polyethylene glycol having molecular weight from 400 Da to 40,000 Da, IDA, Ac-IDA, ADA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, AADA, suitable aliphatic acids, suitable aromatic acids, and heteroaromatic acids. 
     
     
         24 . The peptide molecule of  claim 20 , wherein the C-terminus of the peptide molecule further comprises a modifying group. 
     
     
         25 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 20 , wherein the peptide molecule is a monomer. 
     
     
         26 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 20 , wherein the peptide molecule is a dimer comprising two monomer peptide molecules dimerized by a linker. 
     
     
         27 . (canceled) 
     
     
         28 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 26 , where in the linker is selected from the group consisting of: DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, Triazine, Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. 
     
     
         29 . The peptide molecule or pharmaceutically acceptable salt thereof of  claim 26 , wherein the two peptide molecules are dimerized via their C-termini. 
     
     
         30 . A pharmaceutical composition comprising the peptide molecule or pharmaceutically acceptable salt thereof of  claim 20  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the pharmaceutical composition is formulated for oral delivery. 
     
     
         32 . The pharmaceutical composition of  claim 30 , further comprising an enteric coating. 
     
     
         33 . (canceled) 
     
     
         34 . A method for treating or preventing a disease or condition that is associated with a biological function of integrin β4δ7, the method comprising providing to a subject in need thereof an effective amount of the peptide molecule or pharmaceutically acceptable salt thereof of  claim 20 . 
     
     
         35 . The method of  claim 34 , wherein the disease or condition is selected from the group consisting of Inflammatory Bowel Disease (IBD), adult IBD, pediatric IBD, adolescent 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, primary sclerosing cholangitis, human immunodeficiency virus (HIV) infection in the GI tract, eosinophilic asthma, eosinophilic esophagitis, gastritis, colitis, microscopic colitis and graft versus host disease (GVHD). 
     
     
         36 . The method of  claim 34 , wherein the disease or condition is an inflammatory bowel disease, optionally ulcerative colitis or Crohn's disease. 
     
     
         37 - 38 . (canceled) 
     
     
         39 . The method of  claim 34  wherein the peptide molecule or pharmaceutically acceptable salt thereof inhibits binding of α4β7 to MAdCAM. 
     
     
         40 . The method of  claim 34 , wherein the peptide molecule or pharmaceutically acceptable salt thereof or the pharmaceutical composition is provided to the subject in need thereof at an interval sufficient to ameliorate the condition. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 34 , wherein the peptide molecule or pharmaceutically acceptable salt thereof or pharmaceutical composition is provided as an initial does followed by one or more subsequent doses, and the minimum interval between any two doses is a period of less than 1 day, and wherein each of the doses comprises an effective amount of the peptide molecule or pharmaceutically acceptable salt thereof. 
     
     
         43 . The method of  claim 34 , wherein the effective amount of the peptide molecule or pharmaceutically acceptable salt thereof or the pharmaceutical composition is sufficient to achieve at least one of the following: a) about 50% or greater saturation of MAdCAM binding sites on α4β7 integrin molecules; b) about 50% or greater inhibition of α4β7 integrin expression on the cell surface; and c) about 50% or greater saturation of MAdCAM binding sites on α4β7 molecules and about 50% or greater inhibition of α4β7 integrin expression on the cell surface, wherein i) the saturation is maintained for a period consistent with a dosing frequency of no more than twice daily; ii) the inhibition is maintained for a period consistent with a dosing frequency of no more than twice daily; or iii) the saturation and the inhibition are each maintained for a period consistent with a dosing frequency of no more than twice daily. 
     
     
         44 . The method of  claim 34 , wherein the peptide molecule or pharmaceutically acceptable salt thereof is administered orally. 
     
     
         45 - 46 . (canceled)