Metabolism and Bioactivation: It's Time to Expect the Unexpected.

Improvements in in vitro ADME tools and pharmacokinetic prediction models have shifted attrition rates in early clinical trials from poor exposure to drug safety concerns, such as drug-induced liver injury (DILI). Assessing a new chemical entity's potential for liver toxicity is an important consideration for the success and longevity of potential new drug candidates. Drug metabolism, where reactive intermediates are involved, has been implicated as a cause of DILI and a correlation has been shown between the formation of reactive metabolites and the addition of a black box warning to a drug label. In this work, we will present contemporary examples of the bioactivation of atypical structures usually regarded as safe and often used by medicinal chemists when attempting to avoid bioactivation. Medicinal chemistry strategies used to de-risk bioactivation will be discussed, and an emphasis will be placed on the necessity of a multi-disciplinary approach.