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Chemistry 910 Practical Medicinal Chemistry Dr John Carran Queen’s University Department of Chemistry Background In conjunction with Dale Cameron To develop a course to teach the fundamentals of medicinal chemistry and then to apply them Lecture component Practical component Lecture component Where do drugs act How do drugs bind How are drugs metabolised/consequences How are drugs administered/consequences How are drugs tested SAR/QSAR Molecular modeling (Mike Kuiper, Melbourne, Australia) Lead compound generation/drug design Chemistry and improving activity/drug design Business/intellectual property (Angela Lyon, Parteq, Queen’s University) Process/scale up Clinical trials Case studies Practical component Aim: To mimic an industrial lead compound selection process. Opiate analgesics. Each week for 5 weeks a series of compounds with associated data is released. Each “company” must select one compound to progress in their pipeline to lead compound designation Each company must rationalise their selection process to a Medicinal Chemistry mentor. Mentors Dale Cameron - Migenix Corp Jack Bikker – Wyeth Research Harold Mastalertz – BMS Dinesh Vyas Sheldon Hiebert – BMS Rick Friesen Sheldon Crane – Merck Video conferencing One per week, weeks 7-11 Skype or VSee (Free!) Each “company” has 30 minutes Questions from mentor on selection process / red herrings Teaching component Evaluations on “company” and individual members returned to me “Red Herrings” Sample compound information Effective dose effective dose ED50 behavioural symptoms rhesus monkey intramuscular ED50 0.0014 mg/kg, behavioural symptoms Saimiri sciureus, squirrel monkey intramuscular ED50 0.0018 mg/kg, agonist HEK293 cells transfected with hδOR EC50 727 pmol/l, peristaltic stimulant Sprague-Dawley rat Subcutaneous ED50 0.247 mg/kg, peristaltic stimulant Sprague-Dawley rat Subcutaneous ED50 0.964 mg/kg, Antinociceptive Sprague-Dawley rat Subcutaneous ED50 0.003 mg/kg, {effective dose ED50 Antinociceptive used as methane sulfonate in Macaca mulatta, rhesus monkey ED50 1.0 μg} Activity Narcotic Analgesic Rotation/refraction Molar Refractivity (cm3/mol) 93.15, Calculated Molar Refractivity 9.3645 Blood brain equilibrium 3.66+/-0.513, clearance across BBB into Brain 44.1+/-5.5mL/100g min, logD at pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 8, pH 9, pH 10 [t =25, for neutral and ionic compounds] 0.56, 0.56, 0.56, 0.56, 0.6, 0.84, 1.56, 2.49, 3.23, 3.34, {3.57} Course breakdown Take home assignment (mechanism question in synthesis of Artemisinin) and “midterm” week 6 (handout) (50%) Videoconferencing assignments (5), weeks 7-11 (25% total) Professional project report week 9 (5%) Final poster presentation week 12 (20%) Aims of marked component Midterm exam- examines lecture component material Videoconferencing – communication, rationale, comprehension Report – communication, comprehension Poster presentation – future work, innovation Current enrollment Six students 3 companies (teams) of two students 5 chemists, 1 pharmacologist Ideal enrollment 12+ of mixed groups (chemist + pharmacologist + biochemist) Acknowledgements QCIC Dale Cameron, Dinesh Vyas, Rick Friesen, Jack Bikker Harold Mastalertz, Sheldon Hiebert, Sheldon Crane Angela Lyon, Michael Kuiper Caitlin Latimer (SWEP program, Queen’s University)