Potent and Selective Inhibitors of the TASK-1 Potassium Channel Through Chemical Optimization of a Bis-amide Scaffold
Bioorganic & Medicinal Chemistry Letters
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=16nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.
TASK1, KCNK3, selective potassium channel inhibitor, bis-amide
Flahery, Daniel P.; Simpson, Denise S.; Miller, Meliss; Maki, Brooks E.; Zou, Beiyan; Shi, Jie; Wu, Meng; McManus, Owen B.; Aubé, Jeffery; Li, Min; and Golden, Jennifer E., "Potent and Selective Inhibitors of the TASK-1 Potassium Channel Through Chemical Optimization of a Bis-amide Scaffold" (2014). Pharmaceutical Sciences Faculty Publications. 85.