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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • KCNQ1 Potassium Channel / agonists*
  • KCNQ1 Potassium Channel / metabolism*
  • Molecular Structure
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Tosyl Compounds / chemical synthesis
  • Tosyl Compounds / chemistry
  • Tosyl Compounds / pharmacology*

Substances

  • (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide
  • KCNQ1 Potassium Channel
  • Piperidines
  • Thiazoles
  • Tosyl Compounds