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4-(Aminomethyl) benzamides as novel anti-Ebola agents

4-（氨甲基）苯甲酰胺作为新型抗埃博拉药物

基本信息

批准号：
10207381
负责人：
Lijun Rong
金额：
$ 98.24万
依托单位：
CHICAGO BIOSOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-07 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207381
关键词：
Address Africa African Animal Model Animals Antidotes Antiviral Agents Antiviral Therapy Back Benzamides Binding Biochemical Biological Biological Assay Bioterrorism Categories Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics Clinic Cryoelectron Microscopy Crystallization Development Disease Disease Outbreaks Dose Drug Design Drug Kinetics Ebola Ebola virus Ebola virus envelope glycoprotein Epidemic Escape Mutant Evaluation Exhibits Exposure to Family Family member Fever Filovirus Glycoproteins Goals Hemorrhage Human In Vitro Infection Lead Life Location Marburgvirus Maximum Tolerated Dose Medical Modeling Mus National Institute of Allergy and Infectious Disease Oral Administration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Prevalence Property Rattus Research Route Safety Series Structure Structure-Activity Relationship Symptoms Therapeutic Time Tissues Toxicokinetics Treatment Efficacy United States National Institutes of Health Vaccine Therapy Vaccines Viral Hemorrhagic Fevers Virus Virus Diseases Virus Inhibitors X-Ray Crystallography acute toxicity analog base biodefense cost effective design drug development drug discovery efficacy evaluation genotoxicity improved in vivo in vivo evaluation inhibitor/antagonist insight lead optimization mortality mouse model mutant nanomolar nonhuman primate novel pathogen pre-clinical prophylactic safety study safety testing scaffold scale up small molecule small molecule inhibitor

项目摘要

Ebola (EBOV) and Marburg (MARV) viruses belong to the Filoviridae family and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction after an incubation period of 4-14 days. Due to safety concerns, these viruses are designated as biosafety level 4 agents. Currently, there is no effective vaccine or therapeutic treatment for filoviral infections in humans. Africa has recently (2014-2016) suffered a lethal EBOV epidemic with 27,000 people infected and more than11,000 deaths, underscoring the urgency of antiviral drug discovery and development. This Phase II application proposes to develop potent, small molecule inhibitors, which block entry of EBOV. We have identified compounds that inhibit entry of infectious EBOV/MARV with IC50 values in the nanomolar range. In Phase I, we synthesized structurally diverse analogs of the anti-Ebola CBS1118 hit series based on structure-activity relationships (SARs), to improve potency and selectivity. Prioritized inhibitors were validated in the infectious assay. We investigated the mechanism of action (MOA) of selected candidates, and identified druglike EBOV inhibitors with good in vitro ADME properties. In addition, these inhibitors display excellent pharmacokinetic parameters in mouse studies, following oral administration. In this application, we propose to accomplish the following three specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with EBOV glycoproteins; and (3) evaluate the in vivo efficacy and pharmacokinetics/toxicokinetics of the advanced lead compounds.

埃博拉病毒（EBOV）和马尔堡病毒（MARV）属于丝状病毒科，可导致致命的一种出血热，在潜伏期后表现为广泛的组织破坏， 4-14天出于安全考虑，这些病毒被指定为生物安全4级制剂。目前，没有针对人类丝状病毒感染的有效疫苗或治疗性治疗。非洲最近（2014-2016年）遭受了致命的EBOV流行病，有27，000人感染超过11，000人死亡，强调了抗病毒药物发现的紧迫性，发展该II期申请提出开发有效的小分子抑制剂，其阻止EBOV的进入。我们已经鉴定出抑制感染性病毒进入的化合物， EBOV/MARV，IC 50值在纳摩尔范围内。在第一阶段，我们合成了基于结构-活性关系的抗埃博拉病毒CBS 1118系列的多种类似物（SAR），以提高效力和选择性。在感染性试验中验证了优先选择的抑制剂比色法我们研究了所选候选物的作用机制（MOA），并确定了具有良好的体外ADME性质的药物样EBOV抑制剂。此外，这些抑制剂显示在小鼠研究中，口服给药后的药代动力学参数极佳。在这应用中，我们提出了实现以下三个具体目标：（1）优化铅支架和选择发展候选人;（2）调查的作用机制（MOA）与EBOV糖蛋白的先进先导化合物;和（3）评估体内功效和先进先导化合物的药代动力学/毒理学。