Inhibitors of the Platelet Thrombin Receptor

Abstract

Not that long ago, aspirin, heparin, and warfarin were the only available antithrombotic agents for treating cardiovascular disease patients at risk of thrombotic events. These agents are still used in several places around the world, and it is remarkable how difficult it was to discover other agents that are more effective and/or safer. Since the mid-1980s we have been witnessing an explosion of research on new antithrombotic therapies, resulting in the availability of ticlopidine and clopidogrel (thienopyridine P2Y12-receptor inhibitors), low–molecular-weight heparins (eg, enoxaparin), and intravenous GPIIb/IIIa-receptor inhibitors (abciximab, eptifibatide, and tirofiban), later followed by fondaparinux (a synthetic indirect intravenous anti-Xa agent), bivalirudin (an intravenous direct anti-IIa agent), and more recently, prasugrel (a more potent thienopyridine) (Figure). Figure. The coagulation cascade, platelet activation pathways, and targets of antithrombotic agents. inhib indicates inhibition; LMWH, low–molecular-weight heparin; AT, antithrombin; vWF, von Willebrandt factor; TxA2, thromboxane A2; and ADP, adenosine diphosphate. Articles see pp 1843 and 1854 In the near future, several new oral antithrombotic agents may become available for treating patients with cardiovascular diseases: ticagrelor (the first direct reversible P2Y12 antagonist), dabigatran (an oral direct anti-IIa agent), rivaroxaban (an oral direct anti-Xa agent), and apixaban (also an oral direct anti-Xa agent). Other P2Y12 antagonists (eg, elinogrel) and oral anti-Xa agents (edoxaban, betrixaban, YM150, and TAK-442) are being studied or will be studied in phase-III programs (Figure). New antiplatelet therapies that target pathways not affected by aspirin or P2Y12-receptor antagonists could provide more comprehensive inhibition of platelet activation, and contribute to a greater inhibition of platelet-mediated thrombosis. Inhibition of protease-activated receptor-1 (PAR-1), a receptor for thrombin, is a new attractive approach in the development of better and safer antiplatelet therapy. As shown in the Figure, thrombin is the key effector of the coagulation cascade, but is also …