DataSheet2_Rational Design and Synthesis of 3-Morpholine Linked Aromatic-Imino-1H-Indoles as Novel Kv1.5 Channel Inhibitors Sharing Vasodilation Effects.doc

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.

心房颤动（AF）乃临床最常见的持续性心律失常；临床治疗药物对心房的选择性较低，且在终止心房颤动的同时，可能引发更为严重的室性心律失常。鉴于作为抗心房颤动药物靶点的 Kv1.5 钾通道的未知晶体结构阻碍了新药研发的进一步进展。本研究中，以模拟的 Kv1.5 钾通道的 3D 结构作为药物靶点，基于靶标-配体相互作用分析，设计并合成了系列 3-吗啉连接的芳香族氨基酸取代的 1H-吲哚作为新型 Kv1.5 通道抑制剂。合成路线实用，始于市售原料，且目标化合物的化学结构得到了表征。研究表明，化合物 T16 和 T5（100 μM）对 Kv1.5 通道展现出良好的抑制活性，抑制率分别为 70.8% 和 57.5%，通过膜片钳技术实现。所有化合物均未对其他药物靶点产生脱靶效应，这表明了其在 Kv1.5 通道上的某种选择性。值得注意的是，十二种化合物在体外通过 Myograph 对预收缩的动脉环使用 KCl 或苯肾上腺素（PE）显示出良好的扩张血管活性。化合物 T16 和 T4（100 μM）的血管扩张率甚至超过 90%，这将为抗心房颤动和抗高血压新药研发提供潜在的先导化合物。