Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition-I. Synthesis, structure-activity relationship, and evaluation of substituted (ω-phenyl-ω)-(3-pyridyl)alkenoic acids

A series of arylsulfonamido-substituted ω-phenyl-(ω-(3-pyridyl)alkenoic acids were synthesized and evaluated in vitro for their ability to act as both a thromboxane A2 receptor antagonist (TRA) and thromboxane synthase inhibitor (TSI). Variations of alkenoic acid chain length, olefin geometry, substituent effect on the benzenesulfonamido group, and conformational flexibility of the substituted arylsulfonamido group were examined. Among the various substituents, iodo-substitution gave the most potent compound. Conformational flexibility between the arylsulfonamido group and the phenyl ring attached to the alkenoic acid side chain significantly enhanced the dual activities. The compound (E)-21c was identified as the most potent TRA/TSI (TRA: Kd = 53 nM; TSI: IC50 = 23 nM) in the series studied. The compounds 9c and 10c have indicated that these series of compounds are orally active and are specific TSIs as exhibited by the so-called ‘shunt’ effect on prostacyclin synthesis in vitro.