Drug Discovery for Human African Trypanosomiasis

描述(由申请人提供)：该项目的总体目标是确定治疗非洲人类锥虫病(HAT，昏睡病)的新的临床前候选药物，包括寄生虫进入中枢神经系统时的疾病第二阶段。它仍然是全球最被忽视的疾病之一。由于现有药物具有剧毒或需要非常高的剂量，因此需要新的药物。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，可以杀死导致HAT(布鲁氏锥虫)的寄生虫，并有可能进入中枢神经系统。在初步结果中，我们显示其中一种支架的化合物可以治愈患有急性布氏毛滴虫感染的小鼠。我们将在这五个支架上进行点击到领先的药物化学。这些化合物将被测试其优先杀死锥虫的能力，而不是哺乳动物细胞，最终在HAT啮齿动物模型中的有效性。体外实验将评估水的溶解度，化合物对肝微粒体代谢的稳定性，以及膜的通透性。将进行药代动力学和脑渗透实验，以评估它们是否适合治疗第二阶段感染。我们还将对性能最好的化合物进行初步毒理学研究。希望找到1-2种新化合物，这些化合物可以过渡到治疗HAT的临床试验中，包括疾病的第二阶段。

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.