Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591667 | Bioorganic & Medicinal Chemistry Letters | 2014 | 8 Pages |
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 IC50Â =Â 16Â nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.
Keywords
Related Topics
Physical Sciences and Engineering
Chemistry
Organic Chemistry
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,