Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury
Trent L. Abraham, Bryan H. Norman, Debra Luffer-Atlas, Jeffrey J. Alberts, Boris A. Czeskis, Kenneth C. Cassidy, Steven L. Kuklish, Matthew J. Fisher, Matthew A. Schiffler, Norman E. Hughes
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01806

DOI: 10.1021/acs.jmedchem.7b01806

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