SCH-530348, a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis.

SCH-530348 is a novel antiplatelet agent undergoing development by Schering-Plough Corp for the treatment and prevention of atherothrombosis. The compound is an orally administered himbacine analog that potently antagonizes the platelet thrombin receptor protease-activated receptor 1 (PAR-1), which leaves the procoagulant function of thrombin intact. In preclinical studies, SCH-530348 demonstrated no effect on bleed time or coagulation parameters. In both cynomolgus monkeys and humans, the compound had high bioavailability and inhibited ex vivo TRAP (thrombin receptor-activating peptide)-stimulated platelet aggregation in a potent and long-lasting manner. In a phase II clinical trial of patients undergoing percutaneous coronary intervention, SCH-530348 added to standard therapy with aspirin and clopidogrel did not increase major or minor thrombolysis in myocardial infarction bleeding, and demonstrated a trend toward decreased major adverse cardiovascular events versus placebo. At the time of publication, three phase III trials were underway to assess the efficacy and safety of SCH-530348 for at least 1 year in up to 35,000 patients with acute coronary syndromes or atherosclerosis. The distinct mechanism of action of SCH-530348 allows for cardiovascular protection without the liability of increased bleeding associated with other antiplatelet therapies. Phase III trials in high-risk patients will determine the use of SCH-530348 in cardiological practice.