Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K v7.1 (KCNQ1) potassium channel activator

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

Research output: Contribution to journalArticle

28 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)5936-5941
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2012

Keywords

  • KCNQ1 activator
  • ML277
  • MLPCN probe
  • Potassium channels
  • Voltage-gated ion channels

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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