Advancing Fast-acting Antimalarials that Disrupt Na+ Homeostasis in Parasites

项目摘要 在可预见的未来，抗疟药物仍将是全世界疟疾管理的主要手段。 虽然近年来新的抗疟化合物的管道已经开始看起来很有希望， 抗药性总是若隐若现。这一事实要求继续努力，发现和开发新的 抗疟疾药物。近年来出现的有希望的新抗疟化合物包括 破坏了恶性疟原虫体内Na+的稳态。这些化合物中的两种（螺吲哚酮和 二氢异喹诺酮）已经进展到II期临床试验，并且已经显示出对P. 恶性疟原虫和间日疟原虫感染的体内寄生虫清除时间甚至比青蒿素更快， 最快的抗疟疾药物。值得注意的是，至少有20种不同的化合物， 占药品分发的疟疾和病原体盒中所有抗疟药的约8%， 疟疾风险（MMV）也有破坏恶性疟原虫中Na+稳态的倾向。几行 证据支持所有这些化合物抑制寄生虫编码的Na+泵P型ATP酶的观点 命名为PfATP 4。因此，PfATP 4为非常广泛的小分子提供了高度有吸引力的靶标。 PfATP 4活性化合物在体内对寄生虫的极快清除为这些药物提供了希望。 化合物将成为青蒿素的潜在替代品，世界需要为此做好准备 鉴于青蒿素治疗失败的潜在蔓延。虽然两种PfATP 4活性化合物具有 在临床试验阶段，药物开发的历史建议谨慎地探索备用化合物， 考虑到管道磨损和减少对有价值目标的失败机会。正是基于这种 我们在此提议开展一项药物化学运动， 符合MMV倡导的严格标准的其他临床前候选药物。在过去的十年里， 已经开展了广泛的药物化学活动，以确定高效的PfATP 4活性化合物 属于与临床研究中的两种化合物不同的化学类别。我们的目标是 通过效价、代谢稳定性、物理化学和生物化学指导鉴定临床前候选化合物， 在恶性疟原虫感染的人源化小鼠模型中的药代动力学特性、体内功效和安全性 问题研究这些研究将与PK/PD模拟相结合，以确保化合物符合安全性， 单剂量标准。我们还建议调查最大限度地减少抗性出现的可能性， 探索通过组合不同的化学支架靶向PfATP 4的两个不同结构域的效果。

Project Summary For a foreseeable future antimalarial drugs will remain a mainstay for the management of malaria worldwide. While the pipeline of new antimalarial compounds has begun to look promising in recent years, the specter of drug resistance is always looming. This fact demands continued efforts to discover and develop new antimalarial drugs. Among the promising new antimalarial compounds to emerge in recent years are those that disrupt Na+ homeostasis in Plasmodium falciparum. Two of these compounds (a spiroindolone and a dihydroisoquinolone) have progressed to Phase II clinical trials and have shown to be highly potent against P. falciparum and P. vivax infections with in vivo parasite clearance times that are even faster than artemisinin, the fastest acting antimalarial drug in use. Remarkably, at least 20 distinct chemical classes of compounds, comprising ~8% of all antimalarials present in the Malaria and Pathogen Boxes distributed by Medicines for Malaria Venture (MMV), also have the propensity to disrupt Na+ homeostasis in P. falciparum. Several lines of evidence support the notion that all these compounds inhibit a parasite-encoded Na+-pumping P-type ATPase named PfATP4. Thus, PfATP4 presents a highly attractive target for a very broad range of small molecules. Extraordinarily fast clearance of parasites in vivo by PfATP4-active compounds holds the promise for these compounds to emerge as potential replacement for artemisinin, something the world needs to be prepared for given the potential spread of artemisinin treatment failures. While two PfATP4-active compounds have advanced to clinical trials, the history of drug development advises prudence to explore back-up compounds to account for pipeline attrition and mitigating chances of failure against a valuable target. It is with this background that we are proposing here to conduct a medicinal chemistry campaign that would deliver additional preclinical candidates that meet the stringent criteria advocated by MMV. Over the past decade we have carried out extensive medicinal chemistry campaign to identify highly potent PfATP4-active compounds that belong to different chemical classes than the two compounds under clinical investigations. We aim to identify a pre-clinical candidate compound guided by potency, metabolic stability, physicochemical and pharmacokinetic properties, in vivo efficacy in a humanized mouse model of P. falciparum infection and safety studies. These studies will be allied with PK/PD simulations to ensure a compound that meets safety and single dose criteria. We also propose to investigate the possibility of minimizing resistance emergence by exploring the effects of targeting two different domains of PfATP4 by combination of distinct chemical scaffolds.