2-[3-[2-(4,5-DIPHENYL-2-OXAZOLYL)ETHYL]PHENOXY] ACETIC-ACID (BMY-42393) - A NEW, STRUCTURALLY-NOVEL PROSTACYCLIN PARTIAL AGONIST .1. INHIBITION OF PLATELET-AGGREGATION AND MECHANISM OF ACTION

BMY 42393, 3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid), i s a new prostacyclin partial agonist that inhibited ADP, collagen and thrombin-induced platelet aggregation (IC50 range 0.3 - 2.0 muM). BMY 42393 stimulated platelet adenylate cyclase activity (EC50 = 25 nM), h owever, the maximal activation was 75-80 % of that observed with maxim al iloprost or PGE1. Platelets treated with BMY 42393 showed an elevat ion of cAMP levels and activation of cAMP-dependent protein kinase. BM Y 42393 also inhibited thrombin-induced elevation of intracellular fre e calcium. BMY 42393 competed for radiolabeled iloprost and PGE1 bindi ng to platelet membranes (IC50: 170 nM and 130 nM, respectively); howe ver, it had little effect on radiolabeled PGE2, PGD2, or SQ 29548 bind ing. These studies indicate that BMY 42393 is a novel platelet aggrega tion inhibitor which acts by stimulation of platelet prostacyclin rece ptors to elevate platelet cAMP levels.