Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease
Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent Endonuclease
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DOI：
10.1021/acs.jmedchem.9b00861
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发表时间：
2019-09-12
影响因子：
7.3
通讯作者：
Kawai, Makoto
中科院分区：
文献类型：
--
作者：
Miyagawa, Masayoshi;Akiyama, Toshiyuki;Kawai, Makoto
公开了作为流感Cap依赖性内切核酸酶（CEN）抑制剂的一系列新的氨基甲酰基吡啶酮双环（CAB）化合物的药物化学和构效关系（SAR）。使用对接研究在CAB环系统的C（N）-1、N-3和C-7位置评价取代基效应。在细胞测定中，使用C-7-未取代的CAB（在C-1或N-1位置上具有二苯甲基）获得亚微摩尔EC 50值。发现N-3取代基对于体外血浆蛋白结合效应是关键的，并且CAB-N类似物2 v表现出合理的总清除率（CLtot）。更重要的是，化合物2 v在感染流感病毒的小鼠模型中显示出显著的功效。
The medicinal chemistry and structure activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compounds as influenza Cap dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be critical for the plasma protein binding effect in vitro, and the CAB-N analogue 2v exhibited reasonable total clearance (CLtot). More importantly, compound 2v displayed significant efficacy in a mouse model infected with influenza viruses.