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Clinical experience with antithrombotic drugs acting on purine receptor pathways

Rupture of atherosclerotic plaques and subsequent thrombus formation in coronary arteries are key events in the progression of coronary artery disease and the pathogenesis of acute coronary syndromes. Platelets play a crucial role in this thrombus formation and the success of aspirin in reducing cardiovascular morbidity and mortality has spurred on the search for antiplatelet agents that have an alternative mechanism of action and may, therefore, add to the therapeutic effects of aspirin. The thienopyridines, ticlopidine and clopidogrel, act via metabolites on the platelet ADP receptor subtype designated P2T, and these agents have proven clinical efficacy, either as alternatives to aspirin or, in prevention of coronary stent thrombosis, in combination with aspirin. Potent P2T receptor antagonists 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 ADP‐induced platelet activation, aggregation, and secretion and also antagonises platelet responses to all other agonists in view of the central role of the P2T 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 the thienopyridine clopidogrel. Orally active antagonists are also being developed that may be more effective than the thienopyridines. Drug Dev. Res. 52:202–212, 2001. © 2001 Wiley‐Liss, Inc.