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Mutagenesis. 2018 Sep 5. doi: 10.1093/mutage/gey020. [Epub ahead of print]

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity?

Author information

Sanofi, R&D Preclinical Safety Frankfurt, Industriepark Höchst, Frankfurt am Main, Germany.
Gilead Sciences, Nonclinical Safety and Pathobiology, Foster City, CA, USA.
Leadscope, Inc., Columbus, OH, USA.
Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, NJ, USA.
GlaxoSmithKline Pre-Clinical Development, Ware, Hertfordshire, UK.
Genentech, Inc., Safety Assessment, South San Francisco, CA, USA.
National Institute of Health Sciences, Division of Genetics & Mutagenesis, Kamiyoga, Setagaya-ku, Tokyo, Japan.
Toxicology Division, Eli Lilly and Company, Indianapolis, IN, USA.
Pfizer Worldwide Research and Development, Drug Safety, Genetic Toxicology, Groton, CT, USA.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA.
Xiphora Biopharma Consulting, Bristol, UK.
AstraZeneca, Pharmaceutical Technology and Development, Macclesfield, Cheshire, UK.
Bayer AG, Pharmaceuticals Division, Investigational Toxicology, Muellerstr, Berlin, Germany.


(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class. This article analysed a series of publicly available aromatic N-oxide data in search of supporting information. The article also used a previously developed structure-activity relationship (SAR) fingerprint methodology where a series of aromatic N-oxide substructures was generated and matched against public and proprietary databases, including pharmaceutical data. An assessment of the number of mutagenic and non-mutagenic compounds matching each substructure across all sources was used to understand whether the general class or any specific subclasses appear to lead to mutagenicity. This analysis resulted in a downgrade of the general aromatic N-oxide alert. However, it was determined there were enough public and proprietary data to assign the quindioxin and related chemicals as well as benzo[c][1,2,5]oxadiazole 1-oxide subclasses as alerts. The overall results of this analysis were incorporated into Leadscope's expert-rule-based model to enhance its predictive accuracy.


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