New P2Y(12) inhibitors

Adenosine 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