Minimizing metabolic activation during pharmaceutical lead optimization: progress, knowledge gaps and future directions.

Minimizing the potential for drug candidates to form chemically reactive metabolites that can covalently modify cellular macromolecules represents a rational strategy to reduce the risk of drug-induced idiosyncratic toxicity in humans. In this review, the approaches that are currently available for addressing this issue during the lead optimization phase of drug discovery, their limitations, and future scientific directions that have the potential to address these limitations are discussed.