Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects.
Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects.
复制标题
合理设计和合成 3-吗啉连接的芳香-亚氨基-1H-吲哚作为新型 Kv1.5 通道抑制剂，具有血管舒张作用
DOI：
10.3389/fmolb.2021.805594
复制
发表时间：
2021
影响因子：
5
通讯作者：
Cao HL
中科院分区：
文献类型：
--
作者：
Qin W;Li YH;Tong J;Wu J;Zhao D;Li HJ;Xing L;He CX;Zhou X;Li PQ;Meng G;Wu SP;Cao HL
心房颤动（AF）是临床上最常见的持续性心律失常；临床治疗药物的心房选择性较低，在停止房颤的同时可能引起更严重的室性心律失常。Kv1.5钾通道作为心房肌细胞上具有高选择性的抗房颤药物靶点，其晶体结构的不确定阻碍了新药的进一步开发。本文以模拟Kv1.5的三维结构为药物靶点，基于靶配体相互作用分析，设计合成了一系列3-啉连接的芳香氨基取代1h -吲哚作为新型Kv1.5通道抑制剂。该合成路线从市售原料出发，具有实用性，并对目标化合物的化学结构进行了表征。利用膜片钳技术发现，化合物T16和T5 （100 μM）对Kv1.5通道具有良好的抑制活性，抑制率分别为70.8%和57.5%。所有化合物都没有对其他药物靶标表现出脱靶效应，这表明在Kv1.5通道上有一定的选择性。有趣的是，12种化合物在体外使用KCl或苯肾上腺素（PE）的预收缩动脉环上表现出良好的血管扩张活性。化合物T16和T4 （100 μM）的血管舒张率甚至达到90%以上，为抗房颤和抗高血压新药开发提供了潜在的先导化合物。
Atrial fibrillation (AF) is the most common clinical sustained arrhythmia; clinical therapeutic drugs have low atrial selectivity and might cause more severe ventricle arrhythmias while stopping AF. As an anti-AF drug target with high selectivity on the atrial muscle cells, the undetermined crystal structure of Kv1.5 potassium channel impeded further new drug development. Herein, with the simulated 3D structure of Kv1.5 as the drug target, a series of 3-morpholine linked aromatic amino substituted 1H-indoles as novel Kv1.5 channel inhibitors were designed and synthesized based on target–ligand interaction analysis. The synthesis route was practical, starting from commercially available material, and the chemical structures of target compounds were characterized. It was indicated that compounds T16 and T5 (100 μM) exhibited favorable inhibitory activity against the Kv1.5 channel with an inhibition rate of 70.8 and 57.5% using a patch clamp technique. All compounds did not exhibit off-target effects against other drug targets, which denoted some selectivity on the Kv1.5 channel. Interestingly, twelve compounds exhibited favorable vasodilation activity on pre-contracted arterial rings in vitro using KCl or phenylephrine (PE) by a Myograph. The vasodilation rates of compounds T16 and T4 (100 μM) even reached over 90%, which would provide potential lead compounds for both anti-AF and anti-hypertension new drug development.