Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective Kv7.1 (KCNQ1) potassium channel activator

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Mattmann, Margrith E.^2,4,5  Yu, Haibo^1,6  Lin, Zhihong^1,6  Xu, Kaiping^1,6  Huang, Xiaofang^1,6  Long, Shunyou^1,6  Wu, Meng^1,6  McManus, Owen B.^1,6  Engers, Darren W.^2,4,5  Le, Uyen M.^2,4,5  Li, Min^1,6  Lindsley, Craig W.^2,3,4,5  Hopkins, Corey R.^2,3,4,5 

[1] Johns Hopkins Univ, Dept Neurosci, High Throughput Biol Ctr, Baltimore, MD 21205 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[5] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA

[6] Johns Hopkins Univ, JHICC, Baltimore, MD 21205 USA

关键词: KCNQ1 activator;    MLPCN probe;    Potassium channels;    Voltage-gated ion channels;    ML277;   

DOI  :  10.1016/j.bmcl.2012.07.060

来源: Elsevier

【 摘 要 】

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 (EC50 = 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free