In recent years, there has been a resurgence of interest in drugs that act through covalent modification of their respective biological targets, a mechanism that is appealing due to the prospect of achieving complete inhibition of enzyme activity or blockade of receptor function, as well as an extended duration of action. Historically, reluctance on the part of the pharmaceutical industry to pursue covalent modifiers has been linked to safety concerns associated with the covalent modification of endogeneous cellular constituents by chemically reactive drug metabolites. However, several older drugs that were not designed to act via a covalent mechanism, but which are now known to do so, have proved to be safe and effective therapeutic agents. This has led to a reassessment of the covalent drug approach, and a number of such compounds have now entered clinical development. This presentation will highlight key considerations in covalent drug design, and will compare and contrast covalent drugs with highly reactive, electrophilic drug metabolites.

Overview of covalent modifiers in drug development

246th National Meeting (2013)

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