Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines
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Hunt, Thomas, Howsham, Catherine, Danahay, Henry, Atherton, Hazel, Axford, Jake, Coote, Kevin, Czarnecki, Sarah, Devereux, Nicholas, Hunt, Peter, Paddock, Victoria, Paisley, Derek, Young, Alice and Collingwood, Stephen (2011) Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines. Bioorganic and Medicinal Chemistry Letters. ISSN 0960-894X
Abstract
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 μgkg-1 at 1 h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| 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/5469 |