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

Hunt, Thomas and Howsham, Catherine and Danahay, Henry and Atherton, Hazel and Coote, Kevin and Czarnecki, Sarah and Hunt, Peter and Paisley, Derek (2012) Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines. Bioorganic and Medicinal Chemistry Letters, 22 (8). pp. 2877-2879. ISSN 0960-894X

Abstract

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 12g has an IC50 of 37 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 μgkg-1 at 1 h. 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.

Item Type: Article
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Keywords: ENaC blocker Epithelial Sodium Channel Quaternary amine Cystic Fibrosis Amiloride
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5563

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