Dong Yuxiang, Sonawane Yogesh, Maher Steven P, Zeeman Anne-Marie, Chaumeau Victor, Vantaux Amélie, Cooper Caitlin A, Chiu Francis C K, Ryan Eileen, McLaren Jenna, Chen Gong, Wittlin Sergio, Witkowski Benoît, Nosten François, Sriraghavan Kamaraj, Kyle Dennis E, Kocken Clemens H M, Charman Susan A, Vennerstrom Jonathan L
College of Pharmacy, University of Nebraska Medical Center, 986125 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Center for Tropical and Emerging Global Diseases, University of Georgia, 370 Coverdell Center, 500 D.W. Brooks Drive, Athens, Georgia 30602, United States.
ACS Omega. 2022 Mar 30;7(14):12401-12411. doi: 10.1021/acsomega.2c01099. eCollection 2022 Apr 12.
The catechol derivative RC-12 (WR 27653) () is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard -rhesus monkey () model, but in a small clinical trial, it had no efficacy against hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and liver-stage activity of and its metabolites. Compound had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the -desmethyl, combined -desmethyl/-desethyl, and -didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined -desmethyl/-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage ; however, it was not consistently active against liver-stage . As and all but one of its identified Phase I metabolites had no activity against or liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of or that the exposure of achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the hypnozoites.
儿茶酚衍生物RC-12（WR 27653）（）是少数几种在金标准恒河猴（）模型中对休眠子具有良好活性的非8-氨基喹啉类药物之一，但在一项小型临床试验中，它对休眠子没有疗效。为了更好地了解其药代动力学和药效学特征，并确定潜在的活性代谢物，我们现在描述了它及其代谢物的I期代谢、大鼠药代动力学和肝期活性。化合物在人肝微粒体和猴肝微粒体中的代谢特征不同，数据表明，去甲基、去甲基/去乙基联合以及双去乙基代谢物（或其组合）可能是恒河猴中其肝期抗疟疗效优于人类的原因。事实上，与恒河猴微粒体相比，人肝微粒体中的代谢率要低得多，去甲基/去乙基联合代谢物的形成也是如此，这是唯一测试的对肝期有活性的代谢物；然而，它对肝期的活性并不稳定。由于RC-12及其所有已鉴定的I期代谢物中除一种外对间日疟原虫或肝期疟原虫均无活性，我们认为可能存在其他未鉴定的RC-12活性代谢物，或者在该候选药物已报道的未成功临床试验中达到的RC-12暴露量不足以杀死间日疟原虫休眠子。
