The design of target-specific covalent inhibitors is conceptually attractive because of increased biochemical efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are, in advanced clinical trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. The lecture will examine potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets against the backdrop of toxic drugs associated with the formation of highly reactive metabolites or the ones associated with an innate electrophilic nature. Experimental tactics to mitigate safety risks associated with covalent modifiers will be discussed.

Drug metabolism challenges for the next generation of covalent drugs

246th National Meeting (2013)

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