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

• 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
• 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

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和 感兴趣的SBIR研究主题。600万人感染，8000人死亡 2015年，主要在中美洲和南美洲由晚期疾病引起，如查加斯出血性 发烧。据估计，全球治疗恰加斯病的费用约为70亿美元。查加斯 这种疾病是由寄生的原生锥虫克鲁兹锥虫(T.Cruzi)引起的，并通过蝶形吸虫传播。 在南美洲流行，但由于受感染的移民而传播给生活在其他地方的人 患者和旅行到流行地区。目前还没有疫苗可用，唯一用于治疗的药物是 硝基芳基化合物硝呋莫司和苯硝唑在慢性期作为寄生虫失效 产生抵抗力，也会引起有限的不良事件。通过新药发挥作用的新药 迫切需要机制来消灭患有查加斯病和死亡的慢性患者的寄生虫 疾病。在福克斯大通化学多样性中心(FCCDC)合成的新化合物并在 GSK Tres Cantos开放实验室基金会，西班牙特雷斯·坎托斯，致力于治疗的研究机构 被忽视的热带疾病对克氏锥虫和克氏锥虫的复制都表现出很好的活性 (无鞭毛体)和感染性(锥体鞭毛体)，如在表型筛选分析中发现的。这些化合物 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 照顾硝呋莫司和苯硝唑。此外，到目前为止确定的热门化合物是FCCDC和FCCDC的专利 容易服从进一步的SAR开发，通过药物化学的打击来引领优化。非常 重要的是，到目前为止测试的化合物的活性是杀锥虫的，杀死寄生虫，不仅是 静态，生成活动概况，这在特雷斯诗篇测试设施引起了极大的兴趣。我们 计划通过以下方式开发我们的初步化合物图书馆的活动：1)开发我们小说的SAR 化学型，最终目的是合成治疗急性和慢性恰加氏综合症的开发候选药物 疾病(FCCDC)，2)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 高级销售线索的ADME属性。特雷斯·坎托斯的生物学特征将需要进行四项测试 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查加的分子不同 疾病，我们的分子缺乏通常与毒性和不良反应有关的反应性官能团 效果。在第一阶段结束时，我们希望完全有资格将2-3个新的小分子作为适合于 第二阶段SBIR研究期间的高级分析。该计划的长期目标是完成所有 为治疗查加斯的新药申请研究新药(IND)所需的研究 疾病作为单一疗法或与现有药物联合使用。