2. Academic Validation
  3. Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

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.
Daniel P Flaherty 1,  Denise S Simpson 1,  Melissa Miller 2,  Brooks E Maki 1,  Beiyan Zou 2,  Jie Shi 2,  Meng Wu 3,  Owen B McManus 3,  Jeffrey Aubé 1,  Min Li 2,  Jennifer E Golden 4
Affiliations

Affiliations

  • 1 University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA.
  • 2 Johns Hopkins University, School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
  • 3 Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
  • 4 University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA. Electronic address: jengolden@ku.edu.
PMID: 25017033 DOI: 10.1016/j.bmcl.2014.06.032
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 IC50=16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Keywords

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

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