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PAR1-receptor-antagonism as a new mode of action in anti-platelet therapy Antithrombotic therapy is currently standard in the treatment of acute coronary syndromes but also in several forms of atherosclerotic disease. Among currently available anti-thrombotics, anti-platelet agents inhibit platelet activation and aggregation and thereby interfere with a key process of haemostasis and clot formation. Various platelet-activating agonists are known, mediating their effects via specific platelet surface receptors. Thrombin, the main effector protease in the coagulation cascade, is also the most potent activator of platelet aggregation and thereby plays a critical role in the pathophysiology of thrombosis. Its mode of action is described as proteolytic activation of cell surface receptors known as protease activated receptors (PARs). Among the four known PAR-receptors, PAR-1 is widely distributed in human platelets but also in endothelial and smooth muscle cells. Search for a thrombin receptor antagonist led to the development of SCH530348, a compound showing high affinity to the PAR-1-receptor in in-vitro binding studies. Oral application of SCH530348 in monkeys and humans led to robust inhibition of platelet aggregation following thrombin- or haTRAP-induced platelet aggregation but showed no relevant interference with other compounds like ADP, collagen, a standard thromboxan-mimetic or PAR-4 agonist peptide. In addition to its effects on platelet aggregation, inhibition of PAR-1-mediated mitogenic properties in endothelial and smooth muscle cells might have additional therapeutic utility in the treatment of vascular disorders such as atherosclerosis or restenosis following percutanous vascular interventions. |
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