A local QSAR model based on the stability of nitrenium ions to support the ICH M7 expert review on the mutagenicity of primary aromatic amines

Abstract

Abstract Background Aromatic amines, often used as intermediates for pharmaceutical synthesis, may be mutagenic and therefore pose a challenge as metabolites or impurities in drug development. However, predicting the mutagenicity of aromatic amines using commercially available, quantitative structure–activity relationship (QSAR) tools is difficult and often requires expert review. In this study, we developed a shareable QSAR tool based on nitrenium ion stability. Results The evaluation using in-house aromatic amine intermediates revealed that our model has prediction accuracy of aromatic amine mutagenicity comparable to that of commercial QSAR tools. The effect of changing the number and position of substituents on the mutagenicity of aromatic amines was successfully explained by the change in the nitrenium ion stability. Furthermore, case studies showed that our QSAR tool can support the expert review with quantitative indicators. Conclusions This local QSAR tool will be useful as a quantitative support tool to explain the substituent effects on the mutagenicity of primary aromatic amines. By further refinement through method sharing and standardization, our tool can support the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 expert review with quantitative indicators.

Keywords

• Primary aromatic amine
• Quantitative structure–activity relationship (QSAR)
• In silico
• Nitrenium ion
• ICH M7
• Expert review