title: SCH-530348, a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis.
abstract: 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.
authors.affiliation: University of Kentucky, Department of Pharmaceutical Sciences, Lexington, KY 40536-0082, USA. jhoest2@email.uky.edu
authors.forename: Julie
authors.initials: J
authors.lastname: Oestreich
mesh_terms: D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D044463:Receptor, PAR-1 / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044463:Receptor, PAR-1; C530299:vorapaxar