Drug Discovery for Chagas Disease

项目摘要 拟议研究的长期目标是开发一种治疗恰加斯病的新药， 由寄生虫克氏锥虫引起的一种传染病。据估计， 影响了600万至800万人，主要是在拉丁美洲。这项工作的动机是 目前的治疗就其较差的疗效和耐受性而言。在这个新的应用程序中，我们 将集中在两个化学支架，发现在击中铅项目从一个 以前的NIH支持项目。目前的先导化合物具有有效的抗锥虫 活性（个位数或两位数纳摩尔范围），良好的代谢稳定性，广泛的治疗 窗口和化学处理能力。安全屏幕让人放心。进一步 优化，目标是确定至少一个最终候选人，以提名临床 查加斯病的发展。在研究计划中，两个化合物系列将具有 解决了诸如改善溶解性、代谢稳定性或其他 特色该方法将采用经典的药物化学和迭代轮 化合物设计、合成和测试。每种药物都有超过200种化合物 支架，我们有详细的结构活性关系（SAR），以指导正在进行的工作。的 已知靶点为化合物系列之一（锥虫蛋白酶体）， 计划采用实验方法来确定其他化合物系列的目标。 化合物测试将包括抗锥虫活性、哺乳动物细胞 细胞毒性、溶解度、小鼠药代动力学和小鼠功效模型， 具有确定的通过/不通过标准的筛选级联。安全性研究和大鼠毒理学研究将 在供资期快结束时就最后的主要候选人进行评估。于年底 四年的项目，至少有一个候选药物将被选中进行后期临床前研究 查加斯病的发展。

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.