Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir.,Journal of Medicinal Chemistry

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Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-18 , DOI: 10.1021/acs.jmedchem.9b01900
Irina N Gaisina _{1,

2} , Norton P Peet ₂ , Han Cheng ₃ , Ping Li ₄ , Ruikun Du ₄ , Qinghua Cui ₄ , Kevin Furlong ₅ , Balaji Manicassamy _{5,

6} , Michael Caffrey ₇ , Gregory R J Thatcher ₁ , Lijun Rong ₃

Affiliation

Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.

中文翻译：

4-氨基哌啶作为与奥司他韦协同的甲型流感病毒进入抑制剂的优化。

疫苗接种是控制季节性流感感染最普遍的预防手段。然而，一种有效的疫苗通常需要至少 6 个月的时间来开发用于流行毒株的疫苗。因此，需要新的治疗选择来急性治疗流感感染，以控制这种病毒并防止流行病/大流行病的发展。我们发现了速效、口服生物可利用的酰化 4-氨基哌啶，具有针对病毒血凝素 (HA) 的有效作用机制。我们的数据表明，这些化合物是甲型流感病毒的有效进入抑制剂。我们提出的对接研究表明这些抑制剂在 H5N1 上存在 HA 结合位点。当在流感病毒 H1N1 (A/Puerto Rico/8/1934) 或 H5N1 (A/Vietnam/1203/2004) 毒株和奥司他韦耐药株的感染性试验中评估时，化合物 16 的病毒滴度显着降低常见的 H274Y 突变。此外，化合物 16 在体外与奥司他韦显示出显着的协同活性。

更新日期：2020-03-02

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