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Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-09 00:00:00 , 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

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.

中文翻译:

鉴定和缓解由于临床药物诱发的肝损伤而终止的2-氨基咪唑类微粒体前列腺素E合酶-1抑制剂的反应性代谢产物

发现两种基于2-氨基咪唑的抑制剂LY3031207(1)和LY3023703(2)的微粒体前列腺素E合酶-1(mPGES-1)酶可引起药物性肝损伤(DILI)。我们研究了咪唑环取代以成功减轻反应性代谢物(RM)的形成。这些研究支持以下结论:RM的形成可能在DILI的观察中起作用,并考虑到2-氨基咪唑作为结构警报,这是由于生物激活产生RM的可能性很高。
更新日期:2018-02-09
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