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Discovery of SCH 530348 - A Thrombin Receptor Antagonist (TRA) with Potent Antiplatelet Activity Sam Chackalammil, Distinguished Fellow Schering-Plough Research Institute Abstract: This talk highlights the discovery of SCH 530348, a thrombin receptor antagonist (TRA) which showed exceptional antiplatelet activity in a series of functional assays and non-human primate thrombosis models.1 The original TRA lead was a synthetic analog of the complex natural product himbacine. Optimization of this lead led to the initial development candidate. Despite its promising antiplatelet activity, this candidate had to be dropped from development due to issues related to hepatic enzyme induction in rodents. An exhaustive optimization of the SAR of the tricyclic himbacine core led to the identification of SCH 530348 with excellent safety margin and exceptional antiplatelet activity. In Phase-II clinical studies, SCH 530348 did not show an increase in major or minor bleeding when added to standard anticoagulants and aspirin. Additionally, SCH 530348 showed a numerical reduction in major adverse cardiac events, including periprocedural myocardial infarction in patients undergoing percutaneous coronary intervention. SCH 530348 is currently undergoing two large scale Phase-III clinical studies for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high risk patients.2 Presenter Biography: Curriculum Vitae: Name - Samuel Chackalamannil, Ph.D. Schering-Plough Research Institute 2015 Galloping Hill Rd Kenilworth, NJ 07033 Higher Education B.S. University of Kerala, India M.S. Temple University, Philadelphia Ph.D. Yale University – Thesis advisor: Samuel Danishefsky Present Position - Distinguished Fellow Present Research Activities - Drug discovery research in cardiovascular, metabolic disease and central nervous system areas [Examples: Thrombin receptor antagonist for acute coronary syndrome (in P-III), Adenosine A2a receptor antagonists for Parkinson’s disease (P-II completed), Phosphodiesterase inhibitors for erectile dysfunction (P-II completed) , Cannabinoid-1 receptor antagonists for metabolic disorders, etc.] Past positions Senior Research Fellow (Schering-Plough Research Institute) Research Fellow (Schering-Plough Research Institute Section Leader (Schering-Plough Research Institute) Principal Scientist (Schering-Plough) Senior Scientist (Schering-Plough) Awards R& D Council’s Thomas Alva Edison Patent Award (2008) Schering-Plough Research Institute President’s Award (twice) Publications Total peer-reviewed journal articles – 67 US patents issued – 34 (with several more internationally) Varia Section editor - Current Opinion in Drug Discovery Editorial board – Current Medicinal Chemistry Organizing committee (past) - Chemistry as a Life Science Symposium Invited speaker at major universities and meetings - Most recent: Drew University (Medicinal Chemistry Course), Cornell, U Penn, Rutgers, NSF Wrokshop, ACS Prospectives, GRC ) Online Presentation: http://lifescience.planetconnect.com/ppt/LSPrinceton/wednesday/SAMUEL_CHACKALAMANNIL.ppt