Discovery Toxicology in Lead Optimization

Toxicity remains a leading cause of attrition at all stages of the drug development process. The majority of safety-related attrition occurs preclinically, suggesting that approaches to identify “predictable” preclinical safety liabilities earlier in the drug development process should lead to the design and/or selection of better drug candidates that have increased probabilities of becoming marketed drugs. In this chapter, we discuss how the application of discovery toxicology tools, both new molecular technologies as well as more established approaches such as standard repeat-dose rodent toxicology studies, together with early estimation or simulation of human exposure can identify predictable safety risks earlier in the testing paradigm. The earlier identification and characterization of dose-limiting toxicities will provide chemists and toxicologists with the opportunity to determine structure–toxicity relationships and minimize or circumvent adverse safety liabilities.