The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
J Med Chem. 2024 Aug 22;67(16):14493-14523. doi: 10.1021/acs.jmedchem.4c01241. Epub 2024 Aug 12.
To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound -WJM992, were shown to inhibit PfATP4-associated Na-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, -WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.
为了为开发新的抗疟治疗方法的全球努力做出贡献，我们之前公布了针对 PfATP4 的二氢喹唑啉酮-3-甲酰胺类药物优化的初步发现。在这里，我们报告了改进水溶解度和代谢稳定性，以改善药代动力学特征并提高体内疗效。我们表明，在支架的 8 位上引入杂环系统被发现可以在寄生虫活性、水溶解度和代谢稳定性之间实现最佳平衡。优化的类似物，包括先导化合物-WJM992，被证明可以抑制 PfATP4 相关的 Na-ATP 酶活性，产生与 PfATP4 抑制一致的代谢特征，并对 PfATP4 突变的寄生虫表现出改变的活性。最后，-WJM992 在疟疾小鼠模型中表现出明显的疗效，并阻止配子发育从而防止传播给蚊子。重要的是，需要进一步优化二氢喹唑啉酮类药物，以提供具有改善的药代动力学和耐药风险特征的候选药物。
