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

Autor:	Amberg A; Sanofi, R&D Preclinical Safety Frankfurt, Industriepark Höchst, Frankfurt am Main, Germany., Anger LT; Sanofi, R&D Preclinical Safety Frankfurt, Industriepark Höchst, Frankfurt am Main, Germany., Bercu J; Gilead Sciences, Nonclinical Safety and Pathobiology, Foster City, CA, USA., Bower D; Leadscope, Inc., Columbus, OH, USA., Cross KP; Leadscope, Inc., Columbus, OH, USA., Custer L; Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, NJ, USA., Harvey JS; GlaxoSmithKline Pre-Clinical Development, Ware, Hertfordshire, UK., Hasselgren C; Genentech, Inc., Safety Assessment, South San Francisco, CA, USA., Honma M; National Institute of Health Sciences, Division of Genetics & Mutagenesis, Kamiyoga, Setagaya-ku, Tokyo, Japan., Johnson C; Leadscope, Inc., Columbus, OH, USA., Jolly R; Toxicology Division, Eli Lilly and Company, Indianapolis, IN, USA., Kenyon MO; Pfizer Worldwide Research and Development, Drug Safety, Genetic Toxicology, Groton, CT, USA., Kruhlak NL; U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA., Leavitt P; Bristol-Myers Squibb, Drug Safety Evaluation, New Brunswick, NJ, USA., Quigley DP; Leadscope, Inc., Columbus, OH, USA., Miller S; Leadscope, Inc., Columbus, OH, USA., Snodin D; Xiphora Biopharma Consulting, Bristol, UK., Stavitskaya L; U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA., Teasdale A; AstraZeneca, Pharmaceutical Technology and Development, Macclesfield, Cheshire, UK., Trejo-Martin A; AstraZeneca, Pharmaceutical Technology and Development, Macclesfield, Cheshire, UK., White AT; GlaxoSmithKline Pre-Clinical Development, Ware, Hertfordshire, UK., Wichard J; Bayer AG, Pharmaceuticals Division, Investigational Toxicology, Muellerstr, Berlin, Germany., Myatt GJ; Leadscope, Inc., Columbus, OH, USA.
Jazyk:	angličtina
Zdroj:	Mutagenesis [Mutagenesis] 2019 Mar 06; Vol. 34 (1), pp. 67-82.
DOI:	10.1093/mutage/gey020
Abstrakt:	(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. (© The Author(s) 2018. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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