Trypanocidal Agents that Kill Multiple Stages of the Trypanosoma cruzi Life Cycle

杀死克氏锥虫生命周期多个阶段的杀锥虫剂

基本信息

批准号：
10219137
负责人：
Mark E McDonnell
金额：
$ 30万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2023-04-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219137
关键词：
Acute Adverse event Africa Animal Model Antiparasitic Agents Benznidazole Binding Proteins Biochemical Biological Biological Assay Blinded Cell Survival Cells Central America Cessation of life Chagas Disease Chemicals Chronic Chronic Phase Data Dementia Development Dilated Cardiomyopathy Disease Dose Drug usage Effectiveness Ensure Esophagus Europe Evaluation Excretory function Federal Government Flowcharts Foundations Foxes Free Radicals Generations Goals Heart Heart Aneurysm Human Human Resources Immigration Individual Infection Insecticides Investigational New Drug Application Lead Libraries Life Life Cycle Stages Liver Measures Megacolon Metabolism Microbiology Mitochondria Modality Modeling Mus National Institute of Allergy and Infectious Disease Nervous system structure Neuritis Neurons New Agents Nifurtimox North America Parasites Patient Noncompliance Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Plasma Proteins Property Research Research Priority Resistance development Respiration Review Literature Sales Small Business Innovation Research Grant South America Spain Structure Symptoms System Testing Text Therapeutic Index Toxic effect Travel Triatominae Trypanocidal Agents Trypanosoma cruzi Tumor stage Vaccines Viral Hemorrhagic Fevers absorption analog cost cytotoxicity dosage flu functional group gastrointestinal system improved in vivo in vivo evaluation infection rate interest lead optimization migration mouse model neglect neglected tropical diseases novel novel therapeutics piperidine programs public-private partnership research facility screening side effect small molecule standard of care voucher

项目摘要

Chagas disease is a neglected tropical disease and has been designated as a research priority by NIAID and an SBIR Research Topic of Interest. Six million individuals are infected and 8,000 deaths were caused by in 2015 in mostly Central and South America by advanced forms of the disease such as Chagas hemorrhagic fever. The cost associated with Chagas disease treatment globally is estimated to be ~$7 billion. Chagas disease is caused by the parasitic protist Trypanosoma cruzi (T. cruzi) and spread by Triatominae, or "kissing bugs". It is endemic in South America, but is spread to people living elsewhere due to immigration of infected patients and travel to endemic regions. No vaccine is currently available and the only drugs used to treat, the nitro aryl compounds nifurtimox and benznidazole, lose effectiveness in the chronic phase as the parasite develops resistance and they cause limiting adverse events as well. New medications acting via novel mechanisms are urgently needed to eliminate the parasite in chronic patients suffering and dying from Chagas disease. Novel compounds synthesized at Fox Chase Chemical Diversity Center (FCCDC) and tested at the GSK Tres Cantos Open Lab Foundation in Tres Cantos, Spain, a research facility dedicated to curing neglected tropical diseases, are display excellent activity against the T. cruzi parasite in both its replicative (amastigote) and infective (trypomastigote) forms as found in phenotypic screening assays. The compounds do not act through any known mechanism and display little to no toxicity to host cells, unlike the standard of care nifurtimox and benznidazole. Further, the hit compounds identified so far are proprietary to FCCDC and are readily amenable to further SAR development by medicinal chemistry hit to lead optimization. Very importantly, the activity seen for the compounds tested so far are trypanocidal, killing the parasite, and not only static, generating a profile of activity which has generated great interest at the Tres Cantos testing facility. We plan to exploit the activity of our preliminary compound library by: 1) Developing the SAR of our novel chemotype with the ultimate aim of synthesizing development candidates to treat acute and chronic Chagas disease (FCCDC), 2) characterizing the biochemical properties of the compounds (Tres Cantos), and 3) performing in vivo tests in an acute Chagas Disease mouse model (NYU) as well evaluation and improving ADME properties of advanced leads. The biological characterization at Tres Cantos will entail four assays to gauge anti-parasitic activity and host cell toxicity. Unlike other molecules being researched for treating Chagas disease, our molecules lack reactive functional groups routinely associated with toxicity and adverse side effects. At the end of Phase I we expect to fully qualify 2-3 novel small molecules as leads suitable for advanced profiling in a Phase II SBIR period of study. The long term goal of the program is to complete all of the studies necessary for filing an Investigational New Drug (IND) application for new agents to treat Chagas Disease as monotherapy or in combination with existing agents.

查加斯病是一种被忽视的热带疾病，已被 NIAID 和 NIAID 指定为研究重点 SBIR 感兴趣的研究主题。 600万人被感染，8000人死亡 2015 年，中美洲和南美洲大部分地区出现该病的晚期形式，例如恰加斯出血病发烧。全球与恰加斯病治疗相关的费用估计约为 70 亿美元。恰加斯该病由寄生原生生物克氏锥虫 (T. cruzi) 引起，并通过锥蝽亚科传播，或称“接吻锥虫”。它在南美洲流行，但由于受感染者的移民而传播到居住在其他地方的人们患者和前往流行地区的旅行。目前尚无疫苗可用，唯一用于治疗的药物是硝基芳基化合物硝呋莫司和苯并硝唑，在慢性期作为寄生虫失去效力产生耐药性，也会引起有限的不良事件。通过新颖作用的新药物迫切需要建立机制来消除患有恰加斯病并死亡的慢性患者体内的寄生虫疾病。新型化合物在 Fox Chase 化学多样性中心 (FCCCDC) 合成，并在位于西班牙特雷斯坎托斯的葛兰素史克特雷斯坎托斯开放实验室基金会，是一家致力于治愈的研究机构被忽视的热带疾病，在其复制和繁殖方面都表现出出色的抗克氏锥虫寄生虫活性表型筛选试验中发现的（无鞭毛体）和感染性（锥鞭毛体）形式。化合物不通过任何已知的机制起作用，并且对宿主细胞几乎没有毒性，这与标准不同护理硝呋莫司和苯硝唑。此外，迄今为止发现的热门化合物均为 FCCDC 专有，并且很容易通过药物化学来进一步开发 SAR 来进行先导优化。非常重要的是，迄今为止测试的化合物的活性是杀锥虫，杀死寄生虫，而且不仅静态，生成活动概况，引起了 Tres Cantos 测试设施的极大兴趣。我们计划通过以下方式利用我们的初步化合物库的活动： 1) 开发我们小说的 SAR 化学型的最终目的是合成治疗急性和慢性恰加斯病的候选药物疾病 (FCCCDC)，2) 表征化合物的生化特性 (Tres Cantos)，以及 3) 在急性恰加斯病小鼠模型 (NYU) 中进行体内测试以及评估和改进高级线索的 ADME 属性。 Tres Cantos 的生物学表征将需要进行四项测定测量抗寄生虫活性和宿主细胞毒性。与正在研究的用于治疗恰加斯病的其他分子不同疾病，我们的分子缺乏通常与毒性和不良副作用相关的反应性官能团影响。在第一阶段结束时，我们期望完全有资格将 2-3 个新型小分子作为适合的先导化合物 II 期 SBIR 研究期间的高级分析。该计划的长期目标是完成所有提交治疗恰加斯新药的研究性新药 (IND) 申请所需的研究作为单一疗法或与现有药物联合治疗的疾病。