基于苯磺酰胺的电压门控钠通道Na(v)1.7强效和选择性抑制剂的发现。
The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7.
作者信息
Sun Shaoyi, Jia Qi, Zenova Alla Y, Chafeev Mikhail, Zhang Zaihui, Lin Sophia, Kwan Rainbow, Grimwood Mike E, Chowdhury Sultan, Young Clint, Cohen Charles J, Oballa Renata M
机构信息
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
出版信息
Bioorg Med Chem Lett. 2014 Sep 15;24(18):4397-4401. doi: 10.1016/j.bmcl.2014.08.017. Epub 2014 Aug 14.
The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.
电压门控钠通道Nav1.7是治疗疼痛的一个有趣靶点。人类遗传学研究已确定Nav1.7在疼痛信号传导中的关键作用。在此，我们报告了一系列新型苯磺酰胺类Nav1.7抑制剂的设计与合成。开展了构效关系（SAR）研究以提高Nav1.7活性并将细胞色素P450（CYP）抑制作用降至最低。这些研究工作确定了化合物12k，它是一种高效的Nav1.7抑制剂，对Nav1.5的选择性高达千倍，且对CYP的抑制作用可忽略不计。
Zotero 插件