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：

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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。