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

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.

SUBMITTER: Flaherty DP

PROVIDER: S-EPMC4160056 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Flaherty Daniel P DP Simpson Denise S DS Miller Melissa M Maki Brooks E BE Zou Beiyan B Shi Jie J Wu Meng M McManus Owen B OB Aubé Jeffrey J Li Min M Golden Jennifer E JE

Bioorganic & medicinal chemistry letters 20140619 16

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 repor ...[more]

PMID: 25017033

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