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

埃博拉(EBOV)和马尔堡(Marv)病毒属于丝状病毒科，可导致 出血热的特征是在潜伏期过后广泛的组织破坏 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，还没有针对人类丝状病毒感染的有效疫苗或治疗方法。 非洲最近(2014-2016)经历了致命的埃博拉病毒疫情，有27,000人感染 超过11,000人死亡，突显了抗病毒药物发现和 发展。这一第二阶段的应用建议开发有效的小分子抑制剂， 这阻止了EBOV的进入。我们已经确定了抑制感染性病毒进入的化合物 EBOV/MARV，IC50值在纳摩尔范围内。在第一阶段，我们从结构上合成了 基于结构-活性关系的抗埃博拉CBS1118热门系列的不同类似物 (SARS)，以提高效力和选择性。优先考虑的抑制剂在感染性疾病中得到验证 化验。我们调查了选定候选人的行动机制(MOA)，并确定了 体外ADME性能良好的类药物EBOV抑制剂。此外，这些抑制剂还显示出 口服给药后，在小鼠研究中具有极佳的药代动力学参数。在这 应用方面，我们提出要实现以下三个具体目标：(1)优化引线 脚手架和选择开发候选者；(2)调查 与EBOV糖蛋白结合的先进先导化合物；(3)体内疗效评价 以及高级先导化合物的药代动力学/毒代动力学。

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.