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

Autor:	Boris A. Czeskis, Bryan H. Norman, Norman Earle Hughes, Kenneth C. Cassidy, Kuklish Steven Lee, Debra Luffer-Atlas, Matthew Fisher, Trent L. Abraham, Matthew Allen Schiffler, Jeffrey J. Alberts
Rok vydání:	2018
Předmět:	0301 basic medicine Drug medicine.medical_treatment media_common.quotation_subject Pharmacology Safety-Based Drug Withdrawals Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Humans Structure–activity relationship Prostaglandin-E Synthases media_common Liver injury chemistry.chemical_classification Imidazoles medicine.disease 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis Reactive metabolite Microsome Molecular Medicine Chemical and Drug Induced Liver Injury Microsomal Prostaglandin E Synthase-1 Prostaglandin E
Zdroj:	Journal of Medicinal Chemistry. 61:2041-2051
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5a48ede5c43b6a64048edfaea1a77596 https://doi.org/10.1021/acs.jmedchem.7b01806 Zobrazit plný text záznamu