Potent and Selective Inhibitors of the TASK-1 Potassium Channel Through Chemical Optimization of a Bis-amide Scaffold

Authors

Daniel P. Flahery
Denise S. Simpson, Cedarville UniversityFollow
Meliss Miller
Brooks E. Maki
Beiyan Zou
Jie Shi
Meng Wu
Owen B. McManus
Jeffery Aubé
Min Li
Jennifer E. Golden

Document Type

Article

Publication Date

8-16-2014

Journal Title

Bioorganic & Medicinal Chemistry Letters

Volume

24

Issue

16

First Page

3968

Last Page

3973

DOI

10.1016/j.bmcl.2014.06.032

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=16nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.

Keywords

TASK1, KCNK3, selective potassium channel inhibitor, bis-amide

Recommended Citation

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.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/85