Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the α carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus α4β7 while amide substitution increased the potency of the series without increasing the specificity. Substitution of the β carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus α4β7 but with a significant loss in binding affinity for VLA-4.