4-Aminopiperidines as novel anti-influenza agents

甲型流感病毒属于具有负义的正粘病毒科， 分段RNA基因组，可引起季节性或大流行性流感，发病率高 和显著的死亡率。接种疫苗是最普遍的预防手段， 控制流感感染。然而，有效的疫苗通常需要至少6 几个月的时间来研究流行菌株此外，疫苗接种限制了 治疗免疫功能低下患者的有效性，并且其有效性也 在大流行期间受到限制。目前治疗流感感染的方法都是基于 NA抑制剂（NAIs），而流感M2离子通道阻滞剂（金刚烷胺 和金刚乙胺）不再被推荐，因为所有的流行性感冒 菌株对它们有抵抗力。然而，耐NAI菌株的迅速出现 甲型流感病毒的感染率强烈表明，单独使用NAIs可能不足以 抗流感疗法的有效手段，从而针对 迫切需要其他病毒/宿主因子。此应用程序定义要开发的计划 有效的小分子抑制剂，可阻止甲型流感病毒进入。我们有 已鉴定的抑制感染性甲型流感病毒进入的化合物（IC 50值≤1 µM）。这些命中化合物表现出对H1N1和H5 N1进入的选择性。整体 第一阶段申请的目的是开发这些抑制剂作为潜在的抗流感药物 治疗学本申请将集中于以下三个具体目标：（1） 合成抗流感病毒CBS 1116系列的结构多样的类似物， 结构-活性关系（SAR），以提高效力和选择性。(2)验证 在感染性试验中的主要抑制剂候选物，并研究 抑制剂的作用（MOA）。(3)选择具有体外ADME特性的流感抑制剂 适合静脉注射和口服给药。

Influenza A viruses belong to the orthomyxoviridae family with a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Furthermore, vaccination has limited effectiveness in treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the NA inhibitors (NAIs), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not recommended anymore since all the circulating influenza strains are resistant to them. However, the rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggest that NAIs alone may not be sufficient as an effective means of the anti-flu therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses (IC50 values ≤1 µM). These hit compounds exhibit selectivity for H1N1 and H5N1 entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-flu therapeutics. This application will focus on the following three specific aims: (1) Synthesize structurally diverse analogs of the anti-flu CBS1116 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the inhibitors. (3) Select flu inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.