SUPERCOOPERATIVITY IN PLATELET-AGGREGATION - SUBSTITUTED PYRIDYL ISOXAZOLES, A NEW CLASS OF SUPERCOOPERATIVE PLATELET-AGGREGATION INHIBITORS

The phenomenon of supercooperativity in platelet aggregation is manife sted by the occurence of clear-cut thresholds in dose-response relatio nships; in such cases the Hill coefficient has unusually high values. Approximation, by the Hill equation, of the relationship of the rate o f arachidonate-induced platelet aggregation to the concentrations of e ither the inducer or inhibitors such as substituted pyridyl isoxazoles (synthesized by us), indomethacin, and pinane thromboxane A(2), demon strated that the Hill coefficients ranged from 30 to 100. 3-(3-Pyridyl )-5-phenylisoxazole, which exhibited maximal anti-aggregatory activity among the synthesized compounds, inhibited neither cyclooxygenase nor thromboxane synthase. The compounds affected the signal transduction pathway at/or posterior to the stage of thromboxane A(2) reception.