Chemical Toxicology: A Chemist's Roadmap to Reducing Bioactivation Liabilities in Drug Candidates

Introduction to bioactivation concepts (Guengerich, Vanderbilt) (8:30-11:30 AM)

-Enzymes, including non-CYP enzymes involved in bioactivation
-Cytochrome P450 mechanisms of catalysis and relevance to bioactivation
-The balance of bioactivation vs. detoxication within enzyme systems
-Important polymorphisms and species- or gender-dependent enzyme expression
-Mechanism based CYP inhibition

LUNCH BREAK (11:30-1:00 PM)

Methodologies and strategies for the assessment of bioactivation mediated toxicity (Humphreys, BMS) (1:00-3:00 PM)

-Models for assessment of bioactivation and genotoxicity potential
-Small molecule and large molecule covalent binding assays
-Strategies for incorporating information into drug discovery efforts
-Methods to investigate metabolism mediated toxicity (in vivo methods to determine if metabolism is involved in toxicity, newer -omics methods as predictive tools)

Integrating reactive metabolite liability considerations into drug design during SAR development (Kaushik Mitra and Christine Fandozzi, Merck) (3:00-5:00 PM)

-Structure based liabilities/chemical classes associated with bioactivation
-Strategies and case studies of drug design aimed at reducing bioactivation (cover reducing mechanism-based CYP inhibition, reducing protein and DNA adduct formation)

For more information on the course visit the ACS webpage.