Should the incorporation of structural alerts be restricted in drug design? An analysis of structure-toxicity trends with aniline-based drugs.

Certain idiosyncratic adverse drug reactions (IADRs) can be triggered by electrophilic protein-reactive metabolites that are formed in the process of drug metabolism. While methodologies (e.g., structural alert concept in drug design, glutathione (GSH) trapping, and protein covalent binding) for examining reactive metabolite (RM) formation are available, predicting the IADR potential applying these parameters remains a significant challenge. The present work examines toxicity trends associated with the aniline structural alert in the top 200 prescribed drugs of 2011 and recently approved (2009-2013) small molecule drugs, in relation with 30 aniline-based drugs withdrawn from commercial use or associated with a black box warning for IADRs. The aniline sub-structure was found in several drugs from the toxic, most prescribed, and recently approved category. RMs resulting from the bioactivation of the aniline alert was also noted in the three categories chosen for comparison. A major discriminator between the toxic drugs and the majority of drugs in the most-prescribed list, however, was the daily dose--drugs most frequented associated with IADRs were the ones with higher daily doses (exceeding hundreds of milligrams). A greater tolerance for IADRs was also noted with certain drugs intended to treat rare, unmet medical needs (e.g., cancer). Overall, the analysis suggests that optimization of pharmacologic potency and pharmacokinetics that would lead to a lower daily dose, and therefore, a lower body burden of parent drug/metabolites, should be taken into consideration in drug discovery.