Structure Alerts

Abstract Structure alerts are classes of chemicals, functional groups, or substructures that, when present in drugs or drug candidates, have been linked to preclinical toxicity and/or adverse drug reactions (ADRs) in humans. The assignment of structure alerts, which includes a wide variety of structural types, has mostly emerged from retrospective analyses of drug or drug candidates that have demonstrated toxicity. Some compounds are inherently toxic, while others containing structure alerts manifest toxicity due to metabolism and formation of reactive metabolites. In many cases, the mechanisms associated with toxicity have been hypothesized to be the result of covalent binding of a drug or metabolite to endogenous nucleophiles in proteins and nucleic acids. Strategies to mitigate toxicity due to structure alerts have generally focused on avoidance and/or replacement of the structure alert. However, as many safe and successful drugs contain structure alerts, there is no industry‐wide alignment on which should always be avoided or replaced. It has been demonstrated that ADRs are more likely to occur in higher dose drugs (>100 mg) and more lipophilic drugs (LogP >3). The inclusion of structure alerts in drug candidates that have these liabilities may increase the risk of toxicity.