SCH 530348 Is a Novel Oral Antiplatelet Agent Selective for Protease-Activated Receptor-1 (PAR-1) Receptor Subtype Without Partial Agonist Activity

Objectives Existing antiplatelet therapies target the thromboxane A2 and P2Y12 ADP platelet activation pathways, but do not affect an important pathway triggered by binding of thrombin to the platelet PAR‐1 receptor. The present study evaluated SCH 530348, a novel thrombin receptor antagonist (TRA) selective for PAR‐1, on human platelet function. Methods The effect of SCH 530348 on platelet aggregation in human platelet‐rich plasma was assessed by optical aggregometry in the presence of various agonists. The effect of SCH 530348 on basal and PAR‐1 agonist peptide‐induced expression of P‐selectin, a marker of platelet activation, was also determined. Results SCH 530348 inhibited platelet aggregation induced by the PAR‐1 agonist peptide and α‐thrombin in a dose‐related manner, without affecting platelet aggregation in response to the PAR‐4 agonist peptide, ADP, collagen, and thromboxane mimetic. SCH 530348 effectively inhibited PAR‐1 agonist peptide‐induced P‐selectin expression, but did not affect the basal expression of P‐selectin. Conclusions SCH 530348 selectively inhibits PAR‐1 on human platelets, with no partial agonist activity. SCH 530348 may incrementally reduce pathologic platelet activation not targeted by existing antiplatelet agents, and thus potentially further reduce the risk of ischemic events. This hypothesis is being tested in large clinical trials.