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Bioorg Med Chem Lett. 2012 Jan 15;22(2):929-32. doi: 10.1016/j.bmcl.2011.12.016. Epub 2011 Dec 8.

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

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Novartis Institutes of Biomedical Research, Global Discovery Chemistry, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.


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 IC(50) of 200nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED(50) of 44μgkg(-1) at 1h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers.

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