Development of a cell viability assay to assess drug metabolite structure–toxicity relationships. Issue 16 (15th August 2016)

• Record Type: Journal Article
• Authors: Rana, Payal; Will, Yvonne; Nadanaciva, Sashi; Jones, Lyn H.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 16(2016)
• Page Start: 4003
• Page End: 4006
• Publication Date: 2016-08-15
• Subjects: Metabolic activation -- Reactive metabolite -- Cytochrome P450 -- Drug-induced toxicity -- Structural alerts; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.06.088
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.