Discovery Toxicology In Lead Optimisation
Toxicity is 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 could 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 early application of discovery toxicology tools, both new molecular technologies as well as more established approaches such as standard repeat-dose rodent toxicology studies, can identify predictable safety issues earlier in the testing paradigm. The earlier identification of dose-limiting toxicities will provide chemists and toxicologists the opportunity to characterize the dose-limiting toxicities, determine structure–toxicity relationships and minimise or circumvent adverse safety liabilities.