Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
J Med Chem. 2022 Jan 13;65(1):409-423. doi: 10.1021/acs.jmedchem.1c01586. Epub 2021 Dec 15.
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against , its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.
随着结核病（TB）患者群体耐药性的增加，迫切需要新的药物。理想情况下，新的药物应该通过新的靶点发挥作用，这样它们就不会受到现有治疗方法的临床耐药性的影响。苯并呋喃被确定为一种有潜力的抗结核药物，它可以抑制 Pks13 的硫酯酶结构域。尽管它对有很好的活性，但它的主要缺点是抑制 hERG 心脏离子通道。本文描述了该系列向临床前候选药物的优化过程。尽管在体外改善了 hERG 的副作用，但当新的化合物在离体心脏毒性模型中进行评估时，它们仍然会引起心脏不规则。由于对安全性窗口不足的担忧，进一步的系列开发被停止。然而，多个系列成员的体内活性的证明进一步证实了 Pks13 作为抗结核药物的一个有吸引力的新靶标，并支持开发替代的化学型。
