Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold.
Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold.
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DOI：
10.1016/j.bmcl.2014.06.032
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发表时间：
2014-08-15
影响因子：
2.7
通讯作者：
Golden JE
中科院分区：
文献类型：
--
作者：
Flaherty DP;Simpson DS;Miller M;Maki BE;Zou B;Shi J;Wu M;McManus OB;Aubé J;Li M;Golden JE
ASK-1是一种双孔结构域钾通道，对调节细胞兴奋性非常重要，尤其是在神经元通路中。为了利用Task-I获得治疗益处，其生理作用需要更好的表征;然而，设计避免密切相关的Task-3通道的选择性抑制剂一直具有挑战性。在该研究中，发现一系列双酰胺衍生的化合物与报道的抑制剂相比显示出改善的塔斯克-1对塔斯克-3的选择性。对边缘选择性命中的优化导致类似物35，其在正交电生理学测定中显示出与ASK-3相比具有62倍选择性的ASK-1 IC 50 = 16 nM。
TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.