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

项目摘要 在可预见的未来，抗疟疾药物仍将是全世界疟疾管理的支柱。 虽然近年来新的抗疟疾药物的流水线开始看起来很有希望，但幽灵 耐药性总是隐约可见。这一事实需要继续努力发现和开发新的 抗疟疾药物。在近年来出现的有希望的抗疟疾新化合物中，有一些 这会破坏恶性疟原虫体内的Na+稳态。其中两种化合物(螺吲哚和一种 二氢异喹诺酮类)已进入第二阶段临床试验，并已证明对P. 体内寄生虫清除时间甚至比青蒿素更快的恶性疟原虫和间日疟原虫感染， 使用中见效最快的抗疟疾药物。值得注意的是，至少有20种不同的化合物化学类别， 占疟疾和病原体盒子中所有抗疟疾药物的约8%，由药物分配用于 疟疾风险(MMV)也有破坏恶性疟原虫Na+动态平衡的倾向。几行 有证据表明，所有这些化合物都能抑制寄生虫编码的Na+泵P型ATPase 命名为PfATP4。因此，PfATP4为范围非常广的小分子提供了一个极具吸引力的靶标。 PfATP4活性化合物对体内寄生虫的极快清除为这些 化合物将成为青蒿素的潜在替代品，这是世界需要做好准备的 鉴于青蒿素治疗失败的潜在传播。而两种PfATP4活性化合物具有 随着临床试验的深入，药物开发的历史建议谨慎探索后备化合物以 考虑到管道的损耗，并减少针对有价值的目标的失败机会。是和这个一起的 我们在这里提出的开展药物化学活动的背景将提供 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，我们 开展了广泛的药物化学活动，以确定高效的PfATP4活性化合物 与临床研究中的两种化合物属于不同的化学类别。我们的目标是 根据效力、代谢稳定性、物理化学和化学成分确定临床前候选化合物 人源化恶性疟原虫感染小鼠模型的药代动力学特性、体内疗效和安全性 学习。这些研究将与PK/PD模拟相结合，以确保化合物符合安全和 单次剂量标准。我们还建议研究通过以下方式将耐药性出现降至最低的可能性 探索通过不同的化学支架组合靶向PfATP4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.