Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 3. Synthesis and biological activities of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives and related compounds

A novel series of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyri dyl)alkenoic acid derivatives was discovered as potent dual-acting agents t o block the TXA(2) receptor and to inhibit the thromboxane synthase (TRA/TS I). Synthesis, structure-activity relationship (SAR), and in vitro and in v ivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilici ty of the compounds and to correlate the biological activity with lipophili city of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-c yclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-7-(3-pyridyl)hept-6-enoic acid (14) with K-d = 9.9 +/- 0.4 nM for the thromboxane receptor antagonis m and IC50 = 55.0 +/- 17.9 nM for thromboxane synthase inhibition. The comp ound 14 was a selective TRA/TSI which exhibited desirable characteristics f or oral activity, "shunt" effect to elevate PGI(2) level, and absence of ag onist activity.