Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

Daniel P. Flaherty, Denise S. Simpson, Melissa Miller, Brooks E. Maki, Beiyan Zou, Jie Shi, Meng Wu, Owen B. McManus, Jeffrey Aubé, Min Li, Jennifer E. Golden

Research output: Contribution to journalArticle

Abstract

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 IC 50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Original languageEnglish (US)
Pages (from-to)3968-3973
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number16
DOIs
StatePublished - Aug 15 2014

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Keywords

  • Bis-amide
  • KCNK3
  • Selective potassium channel inhibitor
  • TASK1

ASJC Scopus subject areas

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

Cite this

Flaherty, D. P., Simpson, D. S., Miller, M., Maki, B. E., Zou, B., Shi, J., Wu, M., McManus, O. B., Aubé, J., Li, M., & Golden, J. E. (2014). Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. Bioorganic and Medicinal Chemistry Letters, 24(16), 3968-3973. https://doi.org/10.1016/j.bmcl.2014.06.032