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MARBUG（MARV）病毒属于Filoviridae家族，可能导致致命出血性发作的特征是在孵育期间的广泛组织破坏 4-14天。由于安全问题，这些病毒被指定为生物安全4级药物。目前，没有有效的疫苗或治疗治疗人类的丝状病毒感染。非洲最近（2014-2016）遭受了致命的EBOV流行病，有27,000人感染以及超过11,000人死亡，强调了抗病毒药物发现的紧迫性发展。该II期应用建议开发出有效的小分子抑制剂， EBOV的哪个块进入。我们已经确定了抑制传染性进入的化合物 EBOV/MARV具有纳摩尔范围内IC50值的EBOV/MARV。在第一阶段，我们在结构上合成基于结构活性关系的抗欧博拉CBS1118 HIT系列的不同类似物（SARS），以提高效力和选择性。优先的抑制剂在传染性中得到了验证测定。我们研究了选定候选者的作用机理（MOA），并确定了具有良好体外ADME特性的药物样EBOV抑制剂。另外，这些抑制剂显示口服后，小鼠研究中的优秀药代动力学参数。在这个应用程序，我们建议完成以下三个特定目标：（1）优化铅脚手架和选择候选人；（2）研究作用机理（MOA） EBOV糖蛋白的先进铅化合物；（3）评估体内功效和高级铅化合物的药代动力学/毒性动力学。