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

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3968-73. doi: 10.1016/j.bmcl.2014.06.032. Epub 2014 Jun 19.


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 IC50=16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Keywords: Bis-amide; KCNK3; Selective potassium channel inhibitor; TASK1.

Publication types

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

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Structure-Activity Relationship


  • Amides
  • KCNK9 protein, human
  • Nerve Tissue Proteins
  • Potassium Channel Blockers
  • Potassium Channels, Tandem Pore Domain
  • potassium channel subfamily K member 3