PubMed 22425452

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kir2.3

Title: Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines.

Authors: Thomas Hunt, Hazel C Atherton-Watson, Stephen P Collingwood, Kevin J Coote, Sarah Czarnecki, Henry Danahay, Catherine Howsham, Peter Hunt, Derek Paisley, Alice Young

Journal, date & volume: , 2012 Mar 3 , ,

PubMed link:

We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12 g has an IC(50) of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 1 μg kg(-1) at 1h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride.