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: 10603402
• 负责人: Mark E McDonnell
• 金额: $ 105万
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603402
• 关键词: Acute; Adverse event; Africa; Antiparasitic Agents; Benznidazole; Binding Proteins; Biochemical; Biological Assay; Blinded; Blood; Caring; Cells; Central America; Cessation of life; Chagas Disease; Chemicals; Chronic; Chronic Phase; Collaborations; Data; Dedications; Defecation; Dementia; Deposition; Dilated Cardiomyopathy; Disease; Drug Screening; Drug usage; Effectiveness; Ensure; Esophagus; Europe; Evaluation; Excretory function; Exhibits; Federal Government; Foundations; Free Radicals; G-Protein-Coupled Receptors; Goals; Heart; Heart Aneurysm; Human; Immigration; In Vitro; Individual; Infection; Insect Bites; Insecticides; International; Investigational New Drug Application; Investments; Lead; Legal patent; Life Cycle Stages; Liver Microsomes; Marketing; Mastigophora; Megacolon; Metabolic; Metabolism; Mus; National Institute of Allergy and Infectious Disease; Nervous System; Neuritis; Neurons; New Agents; New York; Nifurtimox; North America; Oral; Parasites; Patients; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Plasma Proteins; Property; Public Health; Qualifying; Recommendation; Research; Research Priority; Resistance development; Resources; Review Literature; Running; Scotland; Series; Site; Small Business Innovation Research Grant; South America; Spain; Stream; Structure; Symptoms; Testing; Text; Toxic effect; Toxicity Tests; Travel; Triatominae; Tropical Disease; Trypanocidal Agents; Trypanosoma cruzi; Universities; Vaccines; Viral Hemorrhagic Fevers; absorption; analog; cost; cytotoxicity; feeding; 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; pre-clinical; programs; research facility; screening; small molecule; vector transmission; voucher

Abstract. 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 Chagas 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". While endemic in South America, it 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 Chagas, 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) have been tested at multiple collaborator sites: GSK Tres Cantos Open Lab Foundation in Tres Cantos, Spain; New York University; University Of Dundee, Scotland; and the Swiss Tropical Public Health Institute, all research facilities dedicated to curing neglected tropical diseases. The analogs tested displayed 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 of action and display little to no toxicity to host cells, unlike the standards of care nifurtimox and benznidazole. Further, in vivo testing in a murine model for Chagas disease (NYU) confirmed potent antiparasitic activity. The lead compounds are proprietary to FCCDC and a provisional U.S. patent application has been filed. The activity seen for the series has generated great interest at the non-profit Drugs for Neglected Diseases Initiative (DNDi). DNDi evaluates many potential international collaborations each year but only selects the most promising for resource investment. Following evaluation of our project, DNDi has committed additional T. cruzi testing gratis at both the University of Dundee and the Swiss Tropical and Public Health Institute in order to evaluate potency and investigate mechanism of action. Our Aims to develop this chemotype from lead compound to preclinical candidate is (1) Optimize the potency by exploring the SAR of our novel lead using iterative medicinal chemistry synthesi, (2) characterize the biochemical properties of the compounds to optimize antiparasitic activity (NYU, DNDi), and (3) perform in vivo tests in acute and chronic Chagas disease mouse models (NYU) as well as evaluate and improve ADME properties of advanced leads as required. The goal of this program is to complete many 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.

抽象。查加斯病是一种被忽视的热带疾病， NIAID和SBIR研究感兴趣的主题。有600万人受到感染，8,000人死亡 2015年，在中美洲和南美洲， 出血热全球治疗恰加斯病的相关费用估计约为70亿美元。 查加斯病是由寄生原生生物克氏锥虫（T。cruzi）并由锥蝽亚科传播，或 “接吻虫”虽然它在南美洲流行，但由于移民，它传播给生活在其他地方的人。 感染病人和前往流行地区。目前还没有疫苗，唯一用于治疗的药物是 恰加斯病是一种硝基芳基化合物硝呋莫司和苯硝哒唑，在慢性期会失去效果，因为 寄生虫会产生抗药性，并且它们也会导致有限的不良事件。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）合成的新型化合物已在 多个合作单位：GSK Tres Cantos开放实验室基金会（位于西班牙Tres Cantos）;纽约大学; 苏格兰邓迪大学和瑞士热带公共卫生研究所，所有研究机构都致力于 治疗被忽视的热带病所测试的类似物显示出优异的抗T.克氏寄生虫 在表型筛选试验中发现其复制型（无鞭毛体）和感染型（锥鞭毛体）。 这些化合物不通过任何已知的作用机制起作用，并且对宿主细胞几乎没有毒性， 与硝呋替莫和苄硝唑的护理标准不同。此外，在鼠模型中进行查加斯病的体内测试， 疾病（纽约大学）证实了有效的抗寄生虫活性。先导化合物为FCCDC专有， 美国临时专利申请已经提交。该系列的活动引起了极大的兴趣 被忽视疾病药物计划（DNDi）DNDi评估了许多潜在的国际 我们每年都进行合作，但只选择最有前途的资源投资。在评价 我们的项目，DNDi已经承诺了额外的T。邓迪大学和瑞士大学都提供免费的克鲁兹测试 热带和公共卫生研究所，以评估效力和研究作用机制。我们的目标 将这种化学型从先导化合物发展为临床前候选物的方法是（1）通过探索 使用迭代药物化学合成我们的新型先导化合物的SAR，（2）表征生物化学 优化抗寄生虫活性的化合物的性质（NYU，DNDi），和（3）在急性感染中进行体内测试。 和慢性恰加斯病小鼠模型（NYU）以及评估和改善 根据需要提供先进的领导。该计划的目标是完成许多必要的研究， 用于治疗南美锥虫病的新药的研究性新药（IND）申请， 与现有的代理商合作。