Potent antiplatelet effects of cyclic clofibric acid (CPIB) analogs on human platelets

Abstract CPIB possesses antiplatelet as well as hypolipidemic activities. Two cyclic CPIB analogs, 6-phenylchroman-2-carboxylic acid (PCCA) and 6-cyclohexylchroman-2-carboxylic acid (CHCCA) were also found to be antagonists of the prostaglandin (PG)-dependent pathway of human platelet activation. PCCA and CHCCA were inhibitors of aggregation (AGG) and secretion (SEC) induced by ADP or epinephrine (E) [second waves only] and arachidonic acid (AA) with IC 50 values ranging from 2.3–8.7 μM for PCCA and 3.7–12.1 μM for CHCCA. Neither compound antagonized the proaggregatory effects of the thromboxane A 2 (TXA 2 ) receptor agonist, U46619. CPIB blocked ADP and E-induced AGG and SEC (IC 50 's > 1200 μM) but not AA- or U46619- induced responses. Only CPIB blocked thrombin-induced AA release. Data showed that PCCA and CHCCA inhibited AA- induced malondialdehyde formation (IC 50 's = 9.3 and 11.3 μM, respectively) and thrombin-induced production of prostaglandin E 2 , prostaglandin F 2α , and TXB 2 with IC 50 's ranging from 2.9 to 13.4 μM. PCCA and CHCCA were at least 200- to 500-fold more potent than CPIB as inhibitors of the PG-dependent pathway of human platelet activation. We conclude that PCCA and CHCCA act by inhibiting platelet cyclooxygenase activity whereas CPIB blocks the activity of phospholipase A 2 . Hypolipidemic PCCA and CHCCA represent a potent class of cyclooxygenase inhibitors which may be more useful than CPIB for treatment of atherosclerotic and thrombotic disorders.