Drug Discovery for Human African Trypanosomiasis

治疗非洲人类锥虫病的药物发现

基本信息

批准号：
8849355
负责人：
Frederick Simmons Buckner
金额：
$ 71.97万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-04 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8849355
关键词：
ABCB1 gene Acute Adverse effects Africa South of the Sahara African Trypanosomiasis Animals Binding Biological Availability Biology Blood - brain barrier anatomy Brain Cell Line Cell Membrane Permeability Central Nervous System Infections Chagas Disease Chemicals Chemistry Clinical Trials Complete Blood Count Cytochromes Disease Dose Drug Kinetics Goals Grant Half-Life Harvest Health Human In Vitro Infection Lead Liquid substance Liver Liver Microsomes Mammalian Cell Measurement Measures Metabolic Metabolism Modeling Mus Neuraxis Oral Organic Synthesis Parasites Patients Penetration Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Potassium Channel Binding Process Proteins Rattus Research Risk Rodent Model Solubility Staging Testing Time Tissues Toxic effect Toxicology Treatment Protocols Trypanosoma Trypanosoma brucei brucei Trypanosoma cruzi Whole Blood analog aqueous cytotoxicity drug candidate drug discovery efficacy testing genotoxicity killings neglect novel pre-clinical research study scaffold scale up

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to identify new pre-clinical drug candidates to treat human African trypanosomiasis (HAT, sleeping sickness), including stage 2 of the disease when the parasites have entered the central nervous system. HAT remains one of the most neglected diseases on the globe. New drugs are needed since existing drugs are highly toxic or require very high dosing. We have identified five structural scaffolds that show sub-micromolar potency to kill the parasite that causes HAT (Trypanosoma brucei) and that have the potential to cross into the central nervous system. In preliminary results, we show that a compound of one of the scaffolds cures mice with acute T. brucei infection. We will carry out hit-to-lead medicinal chemistry on these five scaffolds. The compounds will be tested for their ability to kill trypanosomes preferentially over mammalian cells, and ultimately for efficacy in rodent models of HAT. In vitro experiments will be done to assess aqueous solubility, the stability of compounds to metabolism by liver microsomes, and membrane permeability. Pharmacokinetic and brain penetration experiments will be done to assess their suitability for treating stage 2 infection. Preliminary toxicology studies will also b carried out on our top performing compounds. The hope is to identify 1-2 new compounds that can be transitioned into clinical trials for treating HAT, including stage 2 of the disease.

描述（由申请人提供）：该项目的总体目标是确定新的临床前候选药物来治疗人类非洲锥虫病（帽子，睡眠疾病），包括寄生虫进入中枢神经系统时疾病的第2阶段。帽子仍然是全球最被忽视的疾病之一。由于现有药物有剧毒或需要很高的给药，因此需要新药。我们已经确定了五个结构性支架，它们显示出亚微摩尔效力，以杀死引起HAT的寄生虫（Brucei锥虫），并且有可能跨入中枢神经系统。在初步结果中，我们表明，其中一种支架的一种化合物用急性t. brucei感染治愈小鼠。我们将对这五个脚手架进行命中率对铅化学。这些化合物将通过优先于哺乳动物细胞杀死锥虫的能力，并最终在啮齿动物的HAT模型中杀死锥虫。将进行体外实验以评估水溶性，化合物对肝微粒体代谢的稳定性和膜渗透性。将进行药代动力学和脑穿透实验，以评估其对治疗2期感染的适用性。初步毒理学研究还将在我们的最佳性能化合物上进行。希望是识别1-2种新化合物，这些化合物可以过渡到临床试验，以治疗帽子，包括疾病的第2阶段。