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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：
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.

恰加斯病是一种被忽视的热带病，已被NIAID指定为研究重点