The P2Y 12 receptor as a therapeutic target in cardiovascular disease

Coronary thrombosis complicating rupture of atherosclerotic plaque is the predominant cause of acute coronary syndromes and platelets play a crucial role in this thrombus formation. Whilst aspirin has been successful in reducing cardiovascular morbidity and mortality, appreciation of its limited antiplatelet effects has stimulated the search for more effective antiplatelet agents. The thienopyridines, ticlopidine and clopidogrel, act, via metabolites, on the platelet ADP receptor subtype now designated P2Y(12 )(formerly P(2T), P2T (AC), P2Y (ADP) or P2Y(cyc)) and these agents have proven clinical efficacy. Analogues of the natural P2Y(12) receptor antagonist ATP have been developed that act directly on the receptor and have a rapid onset of action. One such antagonist, AR-C69931MX, is being developed for clinical use. AR-C69931MX is a potent antagonist of ADPinduced platelet activation, aggregation and secretion and also antagonises platelet responses, including procoagulant activity, induced by all other agonists in view of the central role of the P2Y(12) receptor in amplifying platelet responses. Phase II studies of intravenous AR-C69931MX in patients with acute coronary syndromes show that this agent has a rapid onset of action, rapidly achieving steady-state inhibition of platelet aggregation, with a half-life of only a few minutes. AR-C69931MX appears to be safe and well tolerated as adjunctive therapy in these patients, and more effective inhibition of platelet function is achieved than with clopidogrel. Orally active ATP analogues are also being developed that may be more effective than clopidogrel. Limitations of platelet glycoprotein IIb/IIIa antagonists leave scope for development of alternative antiplatelet agents.