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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.

项目总结