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

• DOI: 10.1016/j.bmcl.2012.02.067
• Publication Date: 2012-03-05T19:42:25Z
• Authors: Thomas Hunt; Hazel C. Atherton...; Stephen P. Collin...; Kevin J. Coote; Sarah Czarnecki; Henry Danahay; Catherine Howsham; Peter Hunt; Derek Paisley; Alice Young
• Keywords: Epithelial sodium channel; Amiloride; Chemotype; Guanidine

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.