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Drug Discovery for Chagas Disease

恰加斯病的药物发现

基本信息

批准号：
9927574
负责人：
Frederick Simmons Buckner
金额：
$ 83.42万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-09 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927574
关键词：
Abbreviations Acute Address Affect Affinity Affinity Chromatography African Trypanosomiasis Animal Model Antiparasitic Agents Area Under Curve Binding Proteins Biological Assay Biotin Blood Chagas Disease Characteristics Chemicals Chemistry Chronic Collaborations Communicable Diseases Cytochrome P450 Digit structure Disease Dose Drug Kinetics Ethers Excretory function Exhibits Expression Library Foundations Funding Genes Genetic Genetic study Genomics Goals Growth High-Throughput DNA Sequencing Horns Human Infection Institutes Intravenous Investigational Drugs Latin America Lead Libraries Mammalian Cell Mass Spectrum Analysis Metabolic Metabolism Methods Modeling Modernization Mus Neuraxis Octanes Oral Oral cavity Parasites Parasitic infection Partition Coefficient Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Population Primary Infection Property Proteins Rattus Regimen Research Research Contracts Safety Series Solubility Source Streptavidin Structure-Activity Relationship Techniques Testing Therapeutic Toxic effect Toxicology Treatment Protocols Trypanosoma Trypanosoma cruzi United States National Institutes of Health Universities Washington Water Work absorption analog benzothiazole chemotherapy clinical development crosslink cytotoxicity design drug candidate drug discovery good laboratory practice improved in vitro Assay in vitro activity in vivo imaging system indexing intraperitoneal lead candidate liquid chromatography mass spectrometry multicatalytic endopeptidase complex nanomolar novel therapeutics overexpression preclinical development safety study scaffold screening side effect whole genome

项目摘要

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.

项目概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传染病。恰加斯病估计影响 6-800 万人，主要集中在拉丁美洲。这项工作的动机是由于缺乏目前的治疗方法疗效差且耐受性差。在这个新应用程序中，我们将重点关注在 hit-to-lead 项目中发现的两种化学支架之前 NIH 支持的项目。目前的先导化合物具有有效的抗锥虫作用活性（一位数或两位数纳摩尔范围）、良好的代谢稳定性、广泛的治疗范围窗口和化学处理能力。安全屏幕一直令人放心。随着进一步优化，目标是确定至少一名最终候选人来提名临床恰加斯病的发展。在研究计划中，这两个化合物系列将具有解决的具体问题，例如提高溶解度、代谢稳定性或其他特征。该方法将采用经典的药物化学和迭代循环化合物设计、合成和测试。每种化合物均已制备超过 200 种支架，我们有详细的结构活动关系（SAR）来指导正在进行的工作。这目标已知为其中一种化合物系列（锥虫蛋白酶体），以及两种计划通过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、哺乳动物细胞的体外测定细胞毒性、溶解度、小鼠药代动力学和小鼠功效模型具有明确的通过/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资助期结束时对最终主要候选人进行评估。在这最后为期四年的项目，将至少选择一种候选药物进行后期临床前研究恰加斯病的发展。