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Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines

journal contribution
posted on 2023-06-08, 19:28 authored by Thomas Hunt, Hazel C Atherton-Watson, Jake Axford, Stephen P Collingwood, Kevin J Coote, Brian Cox, Sarah Czarnecki, Henry Danahay, Nick Devereux, Catherine Howsham, Peter Hunt, Victoria Paddock, Derek Paisley, Alice Young
We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC50 of 200 nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 44 µg kg-1 at 1 h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.

History

Publication status

  • Published

Journal

Bioorganic and Medicinal Chemistry Letters

ISSN

0960-894X

Publisher

Elsevier

Issue

2

Volume

22

Page range

929-932

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-01-12

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