Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Molecules. 2020 Mar 20;25(6):1423. doi: 10.3390/molecules25061423.
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
贝达喹啉是一种新型药物，于 2012 年被 FDA 批准用于治疗耐药性结核病（TB）。尽管它对耐药性结核病形式表现出很高的疗效，但由于潜在的严重副作用，其使用受到限制。特别是，贝达喹啉是一种非常亲脂性的化合物，具有相关的长终端半衰期，并对心脏钾 hERG 通道表现出强烈的抑制作用，导致人类 QTc 间期延长，可能导致心律失常。为了解决这些问题，我们开展了一项药物发现计划，以开发一种改良的第二代贝达喹啉类似物。从这个药物化学项目中，选择了一个候选物（TBAJ-876）进行进一步的临床前评估。在这一评估过程中，在几种临床前动物模型中观察到了 TBAJ-876 产生的三个主要代谢物。我们在此报告了我们通过独立定向合成来明确结构表征这三种代谢物的合成努力。
