SYNTHESIS AND EVALUATION OF NOVEL FLUORINATED SULOTROBAN-RELATED SULFONAMIDE DERIVATIVES AS THROMBOXANE A(2) RECEPTOR ANTAGONISTS

A series of sulotroban-related arylsulfonamide derivatives possessing a fluorinated phenoxyacetic acid moiety was synthesized and tested for TXA(2) antagonizing ability on U-46619-induced platelet aggregation o f rabbit platelet-rich plasma. Introduction of one or more fluorine at oms to the phenoxyacetic acid moiety increased this activity. The most potent compound among these compounds was 10c, which was 40-fold more potent (IC50 3.4 x 10(-7) M) than sulotroban. 10c exhibited high acti vity (ID50, 0.14 mg/kg) against a U-46619-induced acute thrombocytopen ia model in mice when orally administrated. These findings and those o f radioligand binding assays with various ligands showed 10c to be a p otent and selective systemic TXA, receptor antagonist.