Pharmaceutical Sciences Faculty Publications

Title

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

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