Liabilities Associated with the Formation of "Hard" Electrophiles in Reactive Metabolite Trapping Screens

Soft electrophiles (e.g., epoxides, quinones, quinone-imines, quinone-methides, etc.) generated via the oxidative bioactivation of phenyl, phenolic, amino-, and alkylphenolic substituents can be trapped with nucleophiles of comparable softness (e.g., glutathione or cysteine) in reactive metabolite screens. In contrast, hard nucleophiles such as cyanide and amines are frequently utilized to trap hard electrophiles (e.g., iminiums and aldehydes) that result from the oxidative bioactivation of cyclic (or acylic) amines and primary alcohols. In some instances, soft sulfydryl nucleophiles have also been utilized to trap aldehydes to yield cyclized thiazolidine adducts. Case studies where hard electrophiles are thought to be responsible for cytochrome P450 inactivation, genotoxicity, and/or target organ toxicity in animals have been presented. The association of hard electrophiles with immune-mediated idiosyncratic adverse drug reactions is less clear given the paucity of available examples and the fact that several marketed drugs containing cyclic amine motifs can generate hard electrophiles via α-carbon ring oxidation. This perspective examines available data associating toxicity with the formation of hard electrophilic intermediates from small molecule drugs/drug candidates. Pragmatic risk mitigation strategies around unwarranted idiosyncratic toxicity risks with drug candidates that generate hard electrophiles are also discussed against the backdrop of marketed agents that possess analogous cyclic amine framework.