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

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:

• R1—X—Y′—Z—R2
• wherein:
• Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO:
• 1);
• 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;
• R1 is R3—CO—;
• R2 is —NR4R5;
• R3 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
• R4 and R5 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) R4 and R5 are not both —H;
• and
• 2) taken together, R4 and R5 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.

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:

• R1—X—Y′—Z—R2
• wherein:
• Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO:
• 1);
• 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;
• R1 is R3—CO—;
• R2 is —NR4R5;
• R3 is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• and
• R4 and R5 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) R4 and R5 are not both —H;
• and
• 2) taken together, R4 and R5 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.

A compound represented by the following structural formula:

• R1—Y′—R2
• wherein:
• Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO:
• 1);
• R1 is R3—CO—;
• R2 is —NR4R5;
• R3 is selected from the group consisting of a lower alkyl group, a substituted lower alkyl group, an aiyl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;
• and
• R4 and R5 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) R4 and R5 are not both —H;
• and
• 2) taken together, R4 and R5 can form a heterocyclic ring;
• and
• wherein optionally Y′ is cyclized.

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:

• R1—Y′—R2
• wherein:
• Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO:
• 1);
• R1 is R3—CO—;
• R2 is —NR4R5;
• R3 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
• R4 and R5 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) R4 and R5 are not both —H;
• and
• 2) taken together, R4 and R5 can form a heterocyclic ring;
• and
• wherein optionally Y′ is cyclized.

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:

• R1—Y′—R2
• wherein:
• Y′ is a pentapeptide having the sequence Leu-Asp-Thr-Ser-Leu (SEQ ID NO:
• 1);
• R1 is R3—CO—;
• R2 is —NR4R5;
• R3 is selected from the group consisting of a lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
• and
• R4 and R5 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) R4 and R5 are not both —H;
• and
• 2) taken together, R4 and R5 can form a heterocyclic ring;
• and
• wherein optionally Y′ is cyclized.