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

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

Author information

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.

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

PMID:
25017033
PMCID:
PMC4160056
DOI:
10.1016/j.bmcl.2014.06.032
[Indexed for MEDLINE]
Free PMC Article

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