New P2Y 12 Inhibitors

Abstract

A denosine diphosphate (ADP) plays a key role in the genesis of physiological platelet-rich hemostatic plugs and of pathological arterial thrombi.1 The transduction of the ADP signal involves its interaction with 2 platelet receptors, the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12 receptor, which belong to the family of purinergic P2 receptors. Concomitant activation of both the Gq and Gi pathways by ADP is necessary to elicit normal platelet aggregation.2 In addition to its role in ADP-induced platelet aggregation, P2Y12 (Figure 1) also mediates the potentiation of platelet secretion induced by strong agonists, which is independent of the formation of large aggregates and thromboxane A2 synthesis2; the stabilization of thrombin-induced platelet aggregates2; shear-induced platelet aggregation2; and the inhibition of the antiplatelet effects of the natural regulator of platelet function, prostacyclin.3 In contrast to P2Y1, P2Y12 has a very selective tissue distribution, making it an attractive molecular target for therapeutic intervention. Indeed, P2Y12 is the target of efficacious antithrombotic agents.1 Figure 1. Central role of P2Y12 in platelet aggregation. ADP, by interacting with P2Y12, a 7-transmembrane receptor that is coupled to the inhibitory G protein Gi, induces platelet aggregation and amplifies the aggregation response that is induced by other agonists or by ADP itself, interacting with its other platelet receptor, P2Y1. In addition, P2Y12 stabilizes the platelet aggregates and amplifies the secretion of platelet dense granules stimulated by secretion-inducing agonists (which are coupled to Gq). Although P2Y12 is coupled to inhibition of adenylyl cyclase (AC) through Gi, this function does not appear to be directly related to P2Y12-mediated platelet activation. However, it could have important implications in vivo, …