Drug Discovery for Chagas Disease

项目摘要 这项拟议研究的长期目标是开发一种治疗恰加斯病的新药， 由克氏锥虫寄生虫引起的传染病。据估计恰加斯病 影响到600-800万人，主要是在拉丁美洲。这项工作的动力来自于……的不足 目前的治疗方法存在疗效和耐受性差的问题。在这个新的应用程序中，我们 将重点介绍在Hit-to-Lead项目中发现的两种化学支架 之前NIH资助的项目。目前的先导化合物有很强的抗锥虫作用。 活性(个位数或两位数纳摩尔范围)，代谢稳定性好，治疗范围广 窗户，和化学易操纵性。安全屏幕一直让人放心。使用进一步的 优化，目标是确定至少一个临床提名的最终候选人 恰加斯病的发展。在研究计划中，两个化合物系列将有 解决的具体问题，如提高溶解度、代谢稳定性或其他 特点。该方法将使用经典的药物化学和迭代回合的 化合物设计、合成和测试。已经为每款产品制造了200种化合物 在支架上，我们有详细的结构活性关系(SAR)来指导正在进行的工作。这个 靶蛋白是已知的一种化合物系列(锥虫蛋白酶体)，以及两种 计划采用实验方法来确定其他化合物系列的目标。 化合物测试将包括体外抗锥虫活性的测试，哺乳动物细胞 细胞毒性、溶解性、小鼠药代动力学和小鼠疗效模型 筛选级联，具有定义的通过/不通过标准。安全性研究和老鼠毒理学研究将 在资助期接近尾声时对最终的主要候选人进行审查。在这个结束的时候 四年计划，至少一种候选药物将被选为晚期临床前药物 恰加斯病的发展。

Project Summary The long-term objective of the proposed research is to develop a new drug for Chagas disease, an infectious disease caused by the parasite Trypanosoma cruzi. Chagas disease is estimated to effect 6-8 million people, mainly in Latin America. The work is motivated by the inadequacy of current therapies with respect to their poor efficacy and tolerability. In this new application we will focus on two chemical scaffolds that were discovered in the hit-to-lead project from a previous NIH supported project. The current lead compounds have potent anti-trypanosomal activity (single or double-digit nanomolar range), good metabolic stability, wide-therapeutic window, and chemical tractability. Safety screens have been reassuring. With further optimization, the goal is to identify at least one final candidate to nominate for clinical development for Chagas disease. In the research plan, the two compound series will have specific issues addressed such as improving solubility, metabolic stability, or other characteristics. The approach will employ classic medicinal chemistry and iterative rounds of compound design, synthesis, and testing. With >200 compounds already made for each of the scaffolds, we have detailed structure activity relationships (SAR) to guide ongoing work. The target is known for one of the compound series (the trypanosome proteasome), and two experimental approaches are planned to identify the target of the other compound series. Compound testing will include in vitro assays for anti-trypanosomal activity, mammalian cell cytotoxicity, solubility, mouse pharmacokinetics, and murine efficacy models following a screening cascade with defined go/no-go criteria. Safety studies and rat toxicology studies will be done towards the end of the funding period on the final lead candidates. At the end of this four-year project, at least one drug candidate will be selected for late-stage preclinical development for Chagas disease.