Development of 4-(aroylamino)piperidine-based entry inhibitors as anti-influenza therapeutics

甲型流感病毒属于正粘病毒科，具有负义、节段性RNA 基因组，可导致季节性或大流行性流感，发病率高，死亡率高。 接种疫苗是控制流感感染的最普遍的预防手段。然而，一个 有效的疫苗通常需要至少六个月的时间才能研制出来。此外，疫苗接种有限。 治疗免疫功能低下患者的有效性，其有效性也是有限的 在大流行期间。目前治疗流感感染的方法都是基于神经氨酸酶。 抑制剂(NAIs；奥司他韦、扎那米韦和帕拉米韦)，而流感M2离子通道阻滞剂 (金刚烷胺和金刚乙胺)现在不推荐使用，因为所有流行的流感毒株 获得了抵抗力。(Xofluza是一种聚合酶酸性核酸内切酶抑制剂，刚刚获得批准 在2018年，在流感季节尚未尝试。)耐NAI菌株的迅速涌现 甲型流感病毒强烈表明，仅有NAI可能不足以作为有效的治疗方法，以及 因此，迫切需要针对其他病毒/宿主因素的新的治疗选择。此应用程序 确定了开发有效的小分子抑制剂的计划，这种抑制剂可以阻止甲型流感病毒的进入。我们 已经确定了抑制传染性甲型流感病毒进入的化合物，其IC50值在 纳摩尔范围。我们已经合成了抗流感系列的结构多样化的类似物，使用 结构-活性关系(SARS)以提高效力和选择性；验证了铅抑制剂 并研究了它们的作用机制(MOA) 抑制剂；以及精选的具有良好体外效力和选择性值的抗流感抑制剂 类药物体内药代动力学特性。在此Fast Track STTR第一阶段和第二阶段应用中，我们建议 四个具体目标：(1)优化牵头脚手架，遴选发展候选者；(2)调查 高级先导化合物与透明质酸蛋白的作用机制；(3)评价 高级先导化合物的药代动力学/毒代动力学；以及(4)临床前开发。

Influenza A viruses belong to the orthomyxoviridae family, and have 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 six months to develop. Furthermore, vaccination has limited effectiveness in the 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 neuraminidase inhibitors (NAIs; oseltamivir, zanamivir and peramivir), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not now recommended since all of the circulating influenza strains have acquired resistance. (Xofluza, a polymerase acidic endonuclease inhibitor, has just been approved in 2018 and is yet untried during a flu season.) The rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as effective 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, with IC50 values in the nanomolar range. We have synthesized structurally diverse analogs of the anti-influenza hit series using structure-activity relationships (SARs) to improve potency and selectivity; validated the lead inhibitor candidates in the infectious assay and investigated the mechanism of action (MOA) of the these inhibitors; and selected anti-influenza inhibitors with excellent in vitro potency and selectivity values and druglike in vivo pharmacokinetic properties. In this Fast Track STTR Phase I &II application, we propose four specific aims: (1) optimize the lead scaffold and select development candidates; (2) investigate the mechanism of action (MOA) of the advanced lead compounds with HA proteins; (3) evaluate the pharmacokinetics/toxicokinetics of the advanced lead compounds; and (4) preclinical development.