Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2013 Nov 1;21(21):6466-76. doi: 10.1016/j.bmc.2013.08.041. Epub 2013 Aug 31.
Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations.
心房颤动（AF）是威胁人类健康的常见心律失常之一。Kv1.5 钾通道被报道为治疗 AF 的一种有效且安全的靶点。在本文中，我们通过修饰我们之前报道的基于药效团模型筛选出的先导化合物 RH01617，设计并合成了三个系列的化合物。所有化合物均通过全贴片式膜片钳技术进行了评估，其中大多数对 Kv1.5 具有很强的抑制活性。化合物 IIIi 和 IIIl 还针对目标选择性以及在分离的大鼠模型中的药效学作用进行了评估。由于具有有前景的药理学行为，化合物 IIIl 值得进一步进行药效学和药代动力学评估。
Zotero 插件