Drug Discovery for Human African Trypanosomiasis

描述（由申请人提供）：本项目的总体目标是确定新的临床前候选药物，用于治疗人类非洲锥虫病（HAT，昏睡病），包括寄生虫进入中枢神经系统时的疾病2期。HAT仍然是地球仪上最被忽视的疾病之一。需要新的药物，因为现有的药物是高毒性的或需要非常高的剂量。我们已经确定了五种结构支架，它们显示出亚微摩尔的效力，可以杀死引起HAT（布氏锥虫）的寄生虫，并且有可能进入中枢神经系统。在初步的结果中，我们表明，一种支架的化合物治愈了患有急性T。布氏杆菌感染我们将在这五个支架上进行药物化学实验。将测试化合物优先于哺乳动物细胞杀死锥虫的能力，并最终测试其在HAT啮齿动物模型中的功效。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渗透实验，以评估其治疗2期感染的适用性。初步毒理学研究也将对我们的顶级性能化合物进行B。希望能够确定1-2种新的化合物，这些化合物可以过渡到临床试验中用于治疗HAT，包括疾病的第2阶段。

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.