PubMed 25017033

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: KCNK3 , KCNK9

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

Authors: 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

Journal, date & volume: Bioorg. Med. Chem. Lett., 2014 Aug 15 , 24, 3968-73

PubMed link:

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.