Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
Bioorg Med Chem Lett. 2021 Aug 1;45:128133. doi: 10.1016/j.bmcl.2021.128133. Epub 2021 May 24.
We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective inshortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide Na inhibitors that bind to the channel voltage sensors, these Na1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.
我们描述了一系列新型芳基磺酰胺的合成和生物学评价，这些化合物表现出对 Na1.5 的强烈抑制作用。与目前用于治疗长 QT 综合征 3（LQT-3）的局部麻醉剂不同，该系列中最有效的化合物（-）-6 对 hERG 和其他心脏离子通道具有高选择性，并且脑/血浆比低，以最大程度减少中枢神经系统副作用。化合物（-）-6 在多能干细胞衍生的心肌细胞（iPSC-CMs）的 LQT-3 综合征药理学模型中也能有效缩短延长的动作电位持续时间（APD）。与大多数结合在通道电压传感器上的芳基磺酰胺 Na 抑制剂不同，这些 Na1.5 抑制剂结合在通道中央孔内的局部麻醉剂结合位点上。
