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ID: ALA4219066
Journal: J Med Chem
Title: Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury.
Authors: Norman BH, Fisher MJ, Schiffler MA, Kuklish SL, Hughes NE, Czeskis BA, Cassidy KC, Abraham TL, Alberts JJ, Luffer-Atlas D.
Abstract: Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.
CiteXplore: 29425457