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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：
10079804
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079804
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.

恰加斯病是一种被忽视的热带疾病，已被NIAID指定为研究重点， SBIR研究感兴趣的主题。600万人感染，8 000人死亡， 2015年主要在中美洲和南美洲由疾病的高级形式，如恰加斯出血发烧全球治疗恰加斯病的相关费用估计约为70亿美元。恰加斯疾病是由寄生原生生物克氏锥虫（Trypanosoma cruzi）（T. cruzi）和传播锥蝽亚科，或“吻臭虫”。它在南美洲流行，但由于感染者的移民，病人和旅行到流行地区。目前没有疫苗可用，唯一用于治疗的药物是硝基芳基化合物硝呋替莫和苄硝哒唑，在慢性期失去效力，会产生耐药性，也会导致有限的不良反应。通过新药物发挥作用的新药迫切需要建立机制，以消除患有和死于恰加斯病的慢性患者体内的寄生虫疾病在福克斯蔡斯化学多样性中心（FCCDC）合成并在美国国家实验室测试的新型化合物 GSK Tres Cantos开放实验室基金会，位于西班牙Tres Cantos，是一家致力于固化的研究机构。被忽视的热带病，对T.克氏寄生虫的复制能力（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，对宿主细胞几乎没有毒性，不像标准的注意硝呋莫司和苄硝哒唑。此外，到目前为止所鉴定的命中化合物是FCCDC专有的，很容易通过药物化学优化进行进一步的SAR开发。非常重要的是，迄今为止测试的化合物的活性是杀锥虫的，杀死寄生虫，静态的，产生了一个活动的配置文件，产生了极大的兴趣，在特雷斯坎托斯测试设施。我们我计划开发我们的初步化合物库的活性：1）开发我们的新的SAR 化学型，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（FCCDC），2）表征化合物的生物化学性质（Tres Cantos），和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善高级电极导线的ADME属性。Tres Cantos的生物学表征将需要四种测定，测量抗寄生虫活性和宿主细胞毒性。与其他正在研究的治疗南美锥虫病的分子不同，疾病，我们的分子缺乏反应性官能团，通常与毒性和不良反应有关。方面的影响.在第一阶段结束时，我们预计将完全合格的2-3个新的小分子作为铅适合在第二阶段SBIR研究期间进行高级分析。该计划的长期目标是完成所有为治疗南美锥虫病的新药提交研究性新药（IND）申请所需的研究单药治疗或与现有药物联合治疗的疾病。