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The inability to predict and quantify the risk of immune-mediated idiosyncratic adverse drug reactions (IADRs) initiated by reactive metabolites (RMs) has led to the evolution of high-throughput screens in preclinical discovery to evaluate their formation with new chemical entities (NCEs), with the ultimate goal of eliminating or reducing the liability through medicinal chemistry design cycles. In addition, structural alerts (SAs) are often excluded from drug design, given their propensity to form RMs. However, numerous marketed drugs contain SAs, form RMs and are devoid of IADRs, indicating that excluding SA-containing and/or RM-positive compounds as a standalone mitigation of IADR risks may be over-exaggerated. A critique of the SA/RM concept as applied in drug discovery and evaluation of the evidence linking them to observed toxicities is presented. Risk mitigation strategies for progression of drug candidates that carry a RM liability are also discussed. Finally, several examples of medicinal chemistry tactics to eliminate RM formation in a preclinical discovery setting are presented.

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