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.

项目摘要对于可预见的未来，抗疟药将仍然是全球疟疾管理的主要主导。尽管近年来，新的抗疟疾化合物的管道已经开始看起来很有前途，但幽灵耐药性总是迫在眉睫。这个事实要求继续努力发现和发展新的抗疟药。近年来，有希望的新抗疟疾化合物是这种破坏了恶性疟原虫中的Na+稳态。这些化合物中的两个（一种螺旋罗酮和一个二氢异喹啉酮已发展为II期临床试验，并已证明对P。恶性疟原虫感染和体内寄生虫清除时间甚至比artemisinin更快使用最快的作用抗疟药。值得注意的是，至少有20种不同的化合物类化合物，占疟疾和病原体中所有抗疟疾物的约8％，由药物分配给疟疾风险（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都抑制寄生虫编码的Na+泵型ATPase的观念名为PFATP4。因此，PFATP4为非常广泛的小分子提供了一个极具吸引力的靶标。 PFATP4活性化合物对寄生虫的寄生虫非常快速清除持有的承诺出现的化合物可以作为阿美氨辛替代的潜在替代品，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活性化合物具有进行了临床试验，药物开发的历史建议审慎探索备用化合物解释管道损耗和减轻对价值目标失败的机会。就是这样我们在这里提议进行药物化学运动的背景活动将提供符合MMV提倡的严格标准的其他临床前候选人。在过去的十年中已经开展了广泛的药物化学运动，以识别高强大的PFATP4活性化合物在临床研究下，该化学类别属于两种化合物。我们的目标确定以效力，代谢稳定性，理化和物理化学和药代动力学特性，在恶性疟原虫感染和安全性的人源化小鼠模型中体内功效研究。这些研究将与PK/PD模拟相结合，以确保符合安全性和单剂量标准。我们还建议调查最大程度地减少抗药性出现的可能性通过组合不同的化学支架的组合探索靶向PFATP4的两个不同域的影响。