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

开发破坏寄生虫 Na 稳态的速效抗疟药

基本信息

批准号：
10055981
负责人：
Sandhya Kortagere
金额：
$ 73.88万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-12 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10055981
关键词：
ATP phosphohydrolase Advocate Antimalarials Artemisinins Back Biology Chemicals Clinical Trials Collaborations Data Development Dose Drug Kinetics Drug Targeting Drug resistance Ensure Failure Future Genetic Goals Half-Life Homeostasis Human India Infection Injectable International Laboratories Lead Malaria Medicine Metabolic Na(+)-K(+)-Exchanging ATPase Names Parasite resistance Parasites Pharmaceutical Chemistry Pharmacology Phase II Clinical Trials Plasmodium Plasmodium falciparum Plasmodium vivax Population Property Pyrazoles Recording of previous events Research Personnel Resistance Resistance development Safety Series Services Solubility Testing Time Treatment Failure Work base benzimidazole chemical synthesis clinical candidate clinical investigation compliance behavior drug development first-in-human genotoxicity humanized mouse improved in vivo in vivo Model inhibitor/antagonist lead optimization mouse model novel pathogen pharmacokinetics and pharmacodynamics pre-clinical safety study scaffold simulation small molecule

项目摘要

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.

项目概要在可预见的未来，抗疟药物仍将是全球疟疾管理的支柱。尽管近年来新的抗疟化合物的研发管线开始看起来很有希望，但耐药性总是迫在眉睫。这一事实要求我们不断努力发现和开发新的抗疟药。近年来出现的有前景的新型抗疟化合物包括破坏恶性疟原虫中 Na+ 的稳态。其中两种化合物（螺吲哚酮和二氢异喹诺酮）已进入 II 期临床试验，并已证明对 P. 恶性疟原虫和间日疟原虫感染体内寄生虫清除时间甚至比青蒿素更快，正在使用的起效最快的抗疟药。值得注意的是，至少有 20 种不同的化学类别的化合物，占药品分发的疟疾和病原体盒中所有抗疟药的约 8% Malaria Venture (MMV) 也有破坏恶性疟原虫 Na+ 稳态的倾向。几行证据支持这样的观点：所有这些化合物都会抑制寄生虫编码的 Na+ 泵 P 型 ATP 酶命名为PfATP4。因此，PfATP4 为广泛的小分子提供了极具吸引力的靶标。 PfATP4 活性化合物能够极快地清除体内寄生虫，这为这些药物带来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考虑到青蒿素治疗失败的潜在传播。虽然两种 PfATP4 活性化合物具有进入临床试验后，药物开发的历史建议谨慎探索备用化合物考虑管道损耗并减少有价值目标失败的可能性。正是有了这个我们在此提议开展药物化学活动的背景符合 MMV 倡导的严格标准的其他临床前候选药物。过去十年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。我们的目标是确定临床前候选化合物，以效力、代谢稳定性、理化和恶性疟原虫感染人源化小鼠模型的药代动力学特性、体内功效和安全性研究。这些研究将与 PK/PD 模拟相结合，以确保化合物满足安全性和单剂量标准。我们还建议研究通过以下方式最大限度地减少耐药性出现的可能性探索通过组合不同的化学支架来靶向 PfATP4 的两个不同结构域的效果。