Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury

  • J Med Chem. 2018 Mar 8;61(5):2041-2051. doi: 10.1021/acs.jmedchem.7b01806.
Bryan H Norman ,  Matthew J Fisher ,  Matthew A Schiffler ,  Steven L Kuklish ,  Norman E Hughes ,  Boris A Czeskis ,  Kenneth C Cassidy ,  Trent L Abraham ,  Jeffrey J Alberts ,  Debra Luffer-Atlas
PMID: 29425457 DOI: 10.1021/acs.jmedchem.7b01806
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.

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