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

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.