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.

抽象的。恰加斯病是一种被忽视的热带疾病，已被指定为研究重点 NIAID和一个感兴趣的SBIR研究主题。600万人感染，8000人死亡 由Chagas于2015年在中美洲和南美洲主要由Chagas等晚期疾病引起 出血热。据估计，全球治疗恰加斯病的费用约为70亿美元。 恰加斯病是由寄生的原生锥虫克鲁兹锥虫(T.ruzi)引起的，并通过螺旋藻传播，或 “接吻的虫子”虽然它在南美洲流行，但由于移民到其他地方，它被传播到其他地方的人 感染患者，并前往流行地区。目前还没有疫苗，唯一用于治疗的药物 Chagas，硝基芳基化合物Nifurtimox和苯硝唑，在慢性期失效，因为 寄生虫产生抗药性，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)合成的新化合物已在 多个合作者网站：GSK特雷斯·坎托斯开放实验室基金会，西班牙特雷斯·坎托斯；纽约大学； 苏格兰邓迪大学和瑞士热带公共卫生研究所，所有研究机构都专门 治愈被忽视的热带病。被测试的类似物对克氏锥虫表现出很好的活性。 在表型筛选分析中发现，在其复制型(无鞭毛体)和感染性(锥虫体)两种形式中。 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表现出很小或没有毒性， 与标准护理不同的是，硝呋莫司和苯硝唑。此外，在查加斯的小鼠模型中进行体内测试 疾病(纽约大学)证实了强大的抗寄生虫活性。这些先导化合物是FCCDC和一家 美国的临时专利申请已经提交。这一系列活动引起了人们的极大兴趣 在非营利性的被忽视疾病药物倡议(DNDI)。DNDI评估了许多潜在的国际 每年的合作，但只选择最有希望的资源投资。在评估之后 我们的项目DNDI已经在邓迪大学和瑞士大学进行了额外的克氏支原体免费测试 热带和公共卫生研究所，以评估效力和调查作用机制。我们的目标 将这种化学类型从先导化合物发展为临床前候选化合物是：(1)通过探索来优化效力 用迭代药物化学合成法合成新型先导化合物的构效关系，(2)生化性质的表征 化合物的性质，以优化抗寄生虫活性(NYU，DNDI)，以及(3)在急性 和慢性Chagas病小鼠模型(NYU)以及评估和改进ADME特性 根据需要提供高级销售线索。该计划的目标是完成许多必要的研究，以提交 研究中的新药(IND)申请治疗恰加斯病的新药物作为单一疗法或 与现有代理相结合。