鉴定（R）-N-（4-（4-甲氧基苯基）噻唑-2-基）-1-对甲苯磺酰基哌啶-2-甲酰胺，ML277，作为一种新型、有效和选择性的 K(v)7.1（KCNQ1）钾通道激活剂。
Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator.
机构信息
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5936-41. doi: 10.1016/j.bmcl.2012.07.060. Epub 2012 Aug 2.
Abstract
A high-throughput screen utilizing a depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the MLSMR collection of over 300,000 compounds. An iterative medicinal chemistry approach was initiated and from this effort, ML277 was identified as a potent activator of KCNQ1 channels (EC(50)=260 nM). ML277 was shown to be highly selective against other KCNQ channels (>100-fold selectivity versus KCNQ2 and KCNQ4) as well as against the distantly related hERG potassium channel.
摘要
利用 KCNQ1 通道去极化触发铊内流的高通量筛选已被开发出来，并用于筛选超过 30 万种化合物的 MLSMR 化合物库。采用迭代药物化学方法，从该研究中发现 ML277 是一种有效的 KCNQ1 通道激活剂（EC50=260 nM）。ML277 对其他 KCNQ 通道（对 KCNQ2 和 KCNQ4 的选择性超过 100 倍）以及与远相关的 hERG 钾通道具有很高的选择性。
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