Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent α4β1 integrin antagonists

Abstract A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the α 4 β 1 integrin. The synthesis and SAR leading up to 3-[3-(1-{2-[3-methoxy-4-(3- o -tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid ( 22 ) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED 50 =2 μg/kg).