Preclinical evaluation of chemically reactive metabolites and mitigation of bioactivation in drug discovery

The formation of reactive metabolites (RMs) is thought to be one of the pathogeneses for some idiosyncratic adverse drug reactions (IADRs) which are considered one of the leading causes of some drug attritions and/or recalls. Minimizing or eliminating the formation of RMs via chemical modification is a useful tactic to reduce the risk of IADRs and time-dependent inhibition (TDI) of cytochrome P450 enzymes (CYPs). The RMs should be carefully handled before making a go–no-go decision. Herein, we highlight the role of RMs in the occurrence of IADRs and CYP TDI, the risk of structural alerts, the approaches of RM assessment at the discovery stage and strategies to minimize or eliminate RM liability. Finally, some considerations for handling a RM-positive drug candidate are suggested.