Inhibitors of MAdCAM-1-mediated interactions and methods of use therefor

Abstract

The present invention provides novel compounds comprising peptide sequences which mimic the conserved amino acid motif LDTSL of MAdCAM-1 and which have groups bonded to the N- and C-termini. Also provided are methods of inhibiting the interaction of a cell bearing a ligand of MAdCAM-1, such as human α4β7, with MAdCAM-1 or a portion thereof (e.g., the extracellular domain), comprising contacting the cell with a compound of the present invention.

What is claimed is:  
     
         1 . A compound represented by the following structural formula: 
       R 1 —X—Y′—Z′R 2   wherein:    Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1), Xaa-Asp-Thr-Ser-Leu (SEQ ID NO: 85), Leu-Xaa-Thr-Ser-Leu (SEQ ID NO: 86), Leu-Asp-Xaa-Ser-Leu (SEQ ID NO: 87), Leu-Asp-Thr-Xaa-Leu (SEQ ID NO: 88), or Leu-Asp-Thr-Ser-Xaa (SEQ ID NO: 89);    Xaa is a naturally-occurring amino acid;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring;    taken together, X, Y′ and Z form a peptide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y′ and Z is cyclized.    
     
     
         2 . The compound of  claim 1  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2-furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, α-naphthylmethyl, 4-heptylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         3 . The compound of  claim 2  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, -CH 2 -2-thienyl, -CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH2-3-furanyl, 3,4-dimethoxybenzyl, and isopentyl.  
     
     
         4 . The compound of  claim 3  wherein Y, is Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1).  
     
     
         5 . The compound of  claim 1  wherein: 
 R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl; and  
 R 5  is —H.  
 
     
     
         6 . The compound of  claim 5  wherein X and Z are each a covalent bond.  
     
     
         7 . The compound of  claim 1  wherein the peptide formed from X, Y, and Z is cyclized.  
     
     
         8 . A compound represented by the following structural formula: 
       R 1 —Y′—R 2   wherein:    Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1), Xaa-Asp-Thr-Ser-Leu (SEQ ID NO:85), Leu-Xaa-Thr-Ser-Leu (SEQ ID NO: 86), Leu-Asp-Xaa-Ser-Leu (SEQ ID NO: 87), Leu-Asp-Thr-Xaa-Leu (SEQ ID NO: 88), or Leu-Asp-Thr-Ser-Xaa (SEQ ID NO: 89);    Xaa is a naturally-occurring amino acid;    R 1  is R 3 —CO—;    R 2  i s —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    wherein optionally Y is cyclized.    
     
     
         9 . The compound of  claim 8  wherein Y′ has the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1).  
     
     
         10 . The compound of  claim 9  wherein R 3  is selected from the group consisting of monocyclic and bicyclic nitrogen-containing heteroaromatic groups, vinyl groups substituted with substituted and unsubstituted aryl and heteroaryl groups, polycarbocyclic aromatic hydrocarbons and oxygen-containing polycyclic aromatic hydrocarbons.  
     
     
         11 . The compound of  claim 9  wherein R 3  is selected from the group consisting of a quinolinyl group, an isoquinolinyl group, an indolyl group, a quinoxalinyl group, a cinnolinyl group, a pyrazinyl group, a styryl group, a stilbyl group, (3-pyridyl)—CH═CH—, a naphthyl group, an anthracyl group, a xanthanyl group, a benzopyranone group and a benzofuranyl group.  
     
     
         12 . A compound represented by the following structural formula: 
       R 1 —X—Y′—Z—R 2   wherein:    Y′ is a tripeptide [AA] 1 -[AA] 2 -[AA] 3  having the sequence Leu-Asp-Thr;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y′ and Z form a peptide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y′ and Z is cyclized.    
     
     
         13 . The compound of  claim 12  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2-furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, α-naphthylmethyl, 4-hepzylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         14 . The compound of  claim 13  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, -CH 2 -2-thienyl, -CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl, 3,4-dimethoxybenzyl, and isopenzyl.  
     
     
         15 . The compound of  claim 12  wherein: 
 R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl; and  
 R 5  is —H.  
 
     
     
         16 . The compound of  claim 12  wherein the peptide formed from X, Y′ and Z is cyclized.  
     
     
         17 . A compound represented by the following structural formula: 
       R 1 —Y′—R 2   wherein:    Y′ is a tripeptide [AA] 1 -[AA] 2 -[AA] 3  having the sequence Leu-Asp-Thr;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring.    
     
     
         18 . The compound of  claim 17  wherein R 3  is selected from the group consisting of phenyl, substituted phenyl, thienyl, substituted thienyl, indolyl, substituted indolyl, pyrimidyl, substituted pyrimidyl, benzofuranyl, substituted benzofuranyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, benzopyranone groups, substituted benzopyranone groups and 3-isoquinolinyl-CO—NH—(CH 2 ) x —, wherein x is an integer from 1-4.  
     
     
         19 . The compound of  claim 18  wherein: 
 R 3  is 3-isoquinolinyl or 2-benzofuranyl;  
 R 4  is —H; and  
 R 5  is benzyl, substituted benzyl, phenethyl, substituted phenethyl, phenpropyl, substituted phenpropyl, heteroaryl-CH 2 —, substituted heteroaryl-CH 2 —, lower alkyl, substituted lower alkyl, cycloalkyl and a group represented by one of the following structural formulas:  
                     
 
     
     
         20 . The compound of  claim 18  wherein: 
 R 3  is 3-isoquinolinyl or 2-benzofuranyl; and  
 R 4  and R 5 , taken together, form a heterocyclic ring selected from the group consisting of pyrrolidinyl, substituted pyrrolidinyl, indoline, isomers of indoline, substituted indoline, substituted isomers of indoline, tetrahydroisoquinoline, substituted tetrahydroisoquinoline, tetrahydroquinoline, substituted tetrahydroquinoline, piperidone, substituted piperidone, piperidine, substituted piperidines, tetrahydro-oxazines and substituted tetrahydro-oxazines.  
 
     
     
         21 . The compound of  claim 17  wherein R 1  is represented by the following structural formula:  
       
         
           
           
               
               
           
         
         wherein:  
         A is selected from the group consisting ofi an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroarylgroup; and  
         n and m are each independently zero or one.  
       
     
     
         22 . A compound represented by the following structural formula: 
       R 1 —X—Y′—Z—R 2   wherein:    Y′ is a dipeptide [AA] 1 -[AA] 2  having the sequence Asp-Thr;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y′ and Z form a pentide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y′ and Z is cyclized with the proviso that, if the peptide formed from X, Y′ and Z is cyclized, the nitrogen at the N-terminus of Y′ is not bonded to a glycine or a sarcosine.    
     
     
         23 . The compound of  claim 22  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, a-naphthylmethyl, 4-heptylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         24 . The compound of  claim 23  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, -CH 2 -2-thienyl, -CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl, 3,4-dimethoxybenzyl, and isopentyl.  
     
     
         25 . The compound of  claim 22  wherein: 
 R 3  is selected from the group consisting of R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl; and  
 R 5  is —H.  
 
     
     
         26 . The compound of  claim 25  wherein X and Z are each a covalent bond.  
     
     
         27 . The compound of  claim 22  wherein the peptide formed from X, Y, and Z is cyclized.  
     
     
         28 . A method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1, comprising administering a therapeutically effective amount of an inhibitor represented by the following structural formula: 
       R 1 —X—Y—Z—R 2   wherein:    Y is a pentapeptide [AA] 1 -[AA] 2 -[AA] 3  -[AA] 4 -[AA] 5  wherein:    [AA] 1  is selected from the group consisting of leucine, cysteine, aspartic acid, glutamic acid, isoleucine, alanine, valine, phenylalanine, glycine, N-methylleucine, serine, threonine, ornithine and lysine;    [AA] 2  is selected from the group consisting of aspartic acid, glutamic acid, phenylalanine and tyrosine;    [AA] 3  is selected from the group consisting of threonine, serine, valine, proline and 4-hydroxyproline;    [AA] 4  is selected from the group consisting of serine, cysteine, aspartic acid, glutamic acid, proline, 4-hydroxyproline, threonine, valine, isoleucine, alanine, glycine, ornithine and lysine; and    [AA] 5  is selected from the group consisting of leucine, isoleucine, N-methylleucine, threonine, ornithine, serine, valine, alanine, glycine, phenylalanine, cysteine, aspartic acid, glutamic acid and lysine;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y and Z form a peptide containing no more than about fifteen amino acids; and    wherein:    optionally the peptide formed by X, Y and Z is cyclized; and    an arginine or an arginine derivative is not bonded to the nitrogen at the N-terminus of Y.    
     
     
         29 . The method of  claim 28  wherein Y is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1), Xaa-Asp-Thr-Ser-Leu (SEQ ID NO: 85), Leu-Xaa-Thr-Ser-Leu (SEQ ID NO: 86), Leu-Asp-Xaa-Ser-Leu (SEQ ID NO: 87), Leu-AsD-Thr-Xaa-Leu (SEQ ID NO: 88), or Leu-Asp-Thr-Ser-Xaa (SEQ ID NO: 89), wherein Xaa is a naturally-occurring amino acid.  
     
     
         30 . The method of  claim 29  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2-furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, a-naphthylmethyl, 4-heptylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         31 . The method of  claim 30  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl, 3,4-dimethoxybenzyl, and isopentyl.  
     
     
         32 . The method of  claim 28  wherein: 
 [AA] 1  is selected from the group consisting of leucine, valine, isoleucine, alanine, glycine, phenylalanine and N-methylleucine;  
 [AA] 2  is selected from the group consisting or aspartic acid, glutamic acid, phenylalanine and tyrosine;  
 [AA] 3  is selected from the group consisting of threonine, serine, valine, proline and 4-hydroxyproline;  
 [AA] 4  is selected from the group consisting of serine, cysteine and threonine; and  
 [AA] 5  is selected from the group consisting of alanine, valine, leucine, isoleucine, alanine, glycine, phenylalanine and N-methylleucine.  
 
     
     
         33 . The method of  claim 32  wherein Y is Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1).  
     
     
         34 . The method of  claim 28  wherein: 
 R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzoth4enyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl;  
 and R 5  is —H.  
 
     
     
         35 . The method of  claim 28  wherein the peptide formed from X, Y and Z is cyclized.  
     
     
         36 . A method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1, comprising administering a therapeutically effective amount of an inhibitor represented by the following structural formula: 
       R 1 —Y′—R 2   wherein:    Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1), Xaa-Asp-Thr-Ser-Leu (SEQ ID NO: 85), Leu-Xaa-Thr-Ser-Leu (SEQ ID NO: 86), Leu-Asp-Xaa-Ser-Leu (SEQ ID NO: 87), Leu-Asp-Thr-Xaa-Leu (SEQ ID NO: 88), or Leu-Asp-Thr-Ser-Xaa (SEQ ID NO: 89);    Xaa s a naturally-occurring amino acid;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    wherein optionally Y is cyclized.    
     
     
         37 . The method of  claim 36  wherein Y′ has the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1).  
     
     
         38 . The method of  claim 37  wherein R 3  is selected from the group consisting of a monocyclic and bicyclic nitrogen-containing heteroaromatic groups, vinyl groups substituted with substituted and unsubstituted aryl and heteroaryl groups, polycarbocyclic aromatic hydrocarbons and oxygen-containing polycyclic aromatic hydrocarbons.  
     
     
         39 . The method of  claim 38  wherein R 3  is selected from the group consisting of a quinolinyl group, an isoquinolinyl group, an indolyl group, a quinoxalinyl group, a cinnolinyl group, a pyrazinyl group, a styryl group, a stilbyl group, (3-pyridyl)—CH═CH—, a naphthyl group, an anthracyl group, a xanthanyl group, a benzopyranone group and a benzoFuranyl group.  
     
     
         40 . The method of  claim 28  wherein the disease is selected from the group consisting of inflammatory bowel disease and insulin-dependent diabetes mellitus.  
     
     
         41 . A method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1, comprising administering a therapeutically effective amount of an inhibitor represented by the following structural formula: 
       R 1 —X—Y′—Z—R 2   wherein:    Y′ is a tripeptide [AA] 1 -[AA] 2 -[AA] 3  having the sequence Leu-Asp-Thr;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R is —NRR;    R 3 is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y′ and Z form a peptide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y′ and Z is cyclized.    
     
     
         42 . The method of  claim 41  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2-furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, α-naphthylmethyl, 4-heptylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         43 . The method of  claim 42  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl, 3,4-dimethoxybenzyl, and isopentyl.  
     
     
         44 . The method of  claim 41  wherein: 
 R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -27thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl;  
 and R 5  is —H.  
 
     
     
         45 . The method of  claim 42  wherein the peptide formed from X, Y′ and Z is cyclized.  
     
     
         46 . The method of  claim 41  wherein the disease is selected from the group consisting of inflammatory bowel disease and insulin-dependent diabetes mellitus.  
     
     
         47 . A method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1, comprising administering a therapeutically effective amount of an inhibitor represented by the following structural formula: 
       R 1 —Y′—R 2   wherein:    Y′ is a tripeptide [AA] 1 -[AA] 2 -[AA] 3  having the sequence Leu-Asp-Thr;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring.    
     
     
         48 . The method of  claim 47  wherein R 3  is selected from the group consisting of phenyl, substituted phenyl, thienyl, substituted thienyl, indolyl, substituted indolyl, pyrimidyl, substituted pyrimidyl, benzofuranyl, substituted benzofuranyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, benzopyranone groups, substituted benzopyranone groups, and 3-isoquinolinyl—CO—NH—(CH 2 ) x , wherein x is an integer from 1-4.  
     
     
         49 . The method of  claim 48  wherein: 
 R 3  is 3-isoquinolinyl or 2-benzofuranyl;  
 R 4  is —H; and  
 R 5  is benzyl, substituted benzyl, phenethyl, substituted phenethyl, phenpropyl, substituted phenpropyl, heteroaryl-CH 2 —, substituted heteroaryl-CH 2 —, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl and a group represented by one of the following structural formulas:  
                     
 
     
     
         50 . The method of  claim 48  wherein: 
 R 3  is 3-isoquinolinyl or 2-benzofuranyl; and  
 R 4  and R 5 , taken together, form a heterocyclic ring selected from the group consisting of pyrollidine and substituted pyrrolidinyl, indoline, isomers of indoline, substituted indoline, substituted isomers of indoline, tetrahydroisoquinoline, substituted tetrahydroisoquincline, tetrahydroquinoline, substituted tetrahydroquinoline, piperidone, substituted piperidone, piperidine, substituted piperidines, tetrahydro-oxazines and substituted tetrahydro-oxazines.  
 
     
     
         51 . The method of  claim 47  wherein R 1  is represented by the following structural formula:  
       
         
           
           
               
               
           
         
         wherein:  
         A is selected from the group consisting of an aryl group, a substituted aryl grrouo, a heteroaryl group and a substituted heteroarylgroup; and  
         n and m are each zero or one.  
       
     
     
         52 . A method of treating an individual suffering from a disease associated with leukocyte infiltration of tissues expressing the molecule MAdCAM-1, comprising administering a therapeutically effective amount of an inhibitor represented by the following structural formula: 
       R 1 —X—Y′—Z—R 2   wherein:    Y′ is a dipeptide [AA] 1 -[AA] 2  having the sequence Asp-Thr;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y′ and Z form a peptide containing no more than about fifteen amino acids; and    wherein the peptide formed from X, Y′ and Z is optionally cyclized with the proviso that, if the peptide formed from X, Y′ and Z is cyclized, the nitrogen at the N-terminus of Y′ is not bonded to a glycine or a sarcosine.    
     
     
         53 . The method of  claim 52  wherein R 3  is selected from the group consisting of triphenylmethyl, diphenylmethyl, 3,5-diphenylphenyl, 2-furanyl, 3-furanyl, 9-xanthenemethyl, 2,2,2-triphenylethyl, 2-anthracene, methyl, cyclopentyl, 2-indolyl, 2-indanyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, cyclohexyl, 5-phenylpentyl, 4-isobutyl-α-methylphenylmethyl, 4-biphenylmethyl, α-naphthylmethyl, 4-heptylphenyl, phenylmethyl, trans 2-phenylethenyl and 2,2,3,3-tetramethylcyclopropyl.  
     
     
         54 . The method of  claim 53  wherein R 4  and R 5  are each independently selected from the group consisting of —H, 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl, 3,4-dimethoxybenzyl, and isopentyl.  
     
     
         55 . The method of  claim 52  wherein: 
 R 3  is selected from the group consisting of diphenylmethyl, triphenylmethyl, trans 2-phenyl-ethylenyl, 2-phenyl-ethynyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl and 3-benzothienyl;  
 R 4  is selected from the group consisting of 2-hydroxyethyl, benzyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzothienyl, 3-benzothienyl, —CH 2 -2-thienyl, —CH 2 -3-thienyl, —CH 2 -2-furanyl, —CH 2 -3-furanyl;  
 and R 5  is —H.  
 
     
     
         56 . The method of  claim 55  wherein X and Z are each a covalent bond.  
     
     
         57 . The method of  claim 52  wherein the peptide formed from X, Y and Z is cyclized.  
     
     
         58 . The method of  claim 52  wherein the disease is selected from the group consisting of inflammatory bowel disease and insulin-dependent diabetes mellitus.  
     
     
         59 . A method of inhibiting the binding of a cell expressing a ligand for MAdCAM-1 on the cell surface to MAdCAM-1 or a portion thereof, comprising contacting the cell with an effective amount of an inhibitor represented by the following structural formula: 
       R 1 —X—Y—Z—R 2   wherein:    Y is a pentapeptide [AA] 1 -[AA] 2 -[AA] 3 -[AA] 4 -[AA] 5  wherein:    [AA] 1  is selected from the group consisting of leucine, cysteine, aspartic acid, glutamic acid, isoleucine, alanine, valine, glycine, N-methylleucine, serine, threonine, ornithine and lysine;    [AA] 2  is selected from the group consisting of aspartic acid, glutamic acid, phenylalanine and tyrosine;    [AA] 3  is selected from the group consisting of threonine, serine, valine, proline and 4-hydroxyproline;    [AA] 4  is selected from the group consisting of serine, cysteine, aspartic acid, glutamic acid, proline, 4-hydroxyproline, threonine, valine, isoleucine, alanine, glycine, ornithine and lysine; and    [AA] 5  is selected from the group consisting of leucine, isoleucine, N-methylleucine, threonine, ornithine, serine, valine, alanine, glycine, phenylalanine, cysteine, aspartic acid, glutamic acid and lysine;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y and Z form a peptide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y and Z is cyclized.    
     
     
         60 . The method of  claim 59  wherein Y is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO: 1), Xaa-Asp-Thr-Ser-Leu (SEQ ID NO: 85), Leu-Xaa-Thr-Ser-Leu (SEQ ID NO: 86), Leu-Asp-Xaa-Ser-Leu (SEQ ID NO: 87), Leu-Asp-Thr-Xaa-Leu (SEQ ID NO: 88), or Leu-Asp-Thr-Ser-Xaa (SEQ ID NO: 89), wherein Xaa is a naturally-occurring amino acid.  
     
     
         61 . The method of  claim 60  wherein the ligand is human α4β7 integrin.  
     
     
         62 . The method of  claim 61  wherein the cell is a leukocyte.  
     
     
         63 . The method of  claim 62  wherein MAdCAM-1 is expressed on the surface of an endothelial cell.  
     
     
         64 . The method of  claim 59  wherein the peptide formed from X, Y and Z is cyclized.  
     
     
         65 . A method of inhibiting the binding of a cell expressing a ligand of MAdCAM-1 to MAdCAM-1 or a portion thereof, comprising contacting the cells with an inhibitory amount of a compound represented by the following structural formula: 
       R 1 —X—Y′—Z—R 2   wherein:    Y is a dipeptide [AA] 1 -[AA] 2  having the sequence Asp-Thr or a tripeptide [AA] 1 -[AA] 2 - [AA] 3  having the sequence Leu-Asp-Thr;    X and Z are independently chosen from the group consisting of a covalent bond, an amino acid or a peptide, wherein each amino acid in X and Z is independently selected from the group of naturally occurring amino acids;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can form a heterocyclic ring; and    taken together, X, Y′ and Z form a peptide containing no more than about fifteen amino acids; and    wherein optionally the peptide formed from X, Y′ and Z is cyclized with the proviso that, if the peptide formed from X, Y′ and Z is cyclized and if Y′ is Asp-Thr, the nitrogen at the N-terminus of Y′ is not bonded to a glycine or a sarcosine.    
     
     
         66 . The method of  claim 65  wherein the ligand is human α4β7 integrin.  
     
     
         67 . The method of  claim 66  wherein the cell is a leukocyte.  
     
     
         68 . The method of  claim 67  wherein MAdCAM-1 is expressed on the surface of an endothelial cell.  
     
     
         69 . The method of  claim 65  wherein the peptide formed from X, Y′ and Z is cyclized.  
     
     
         70 . A compound represented by the following structural formula: 
       R 1 —Y′—R 2   wherein:    Y′ is a dipeptide [AA] 1 -[AA] 2  having the sequence Asp-Thr;    R 1  is R 3 —CO—;    R 2  is —NR 4 R 5 ;    R 3  is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group; and    R 4  and R 5  are each independently selected from the group consisting of hydrogen, a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, wherein:    1) R 4  and R 5  are not both —H; and    2) taken together, R 4  and R 5  can feorm a heterocyclic ring.