1. Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines.
- Author
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Hunt T, Atherton-Watson HC, Collingwood SP, Coote KJ, Czarnecki S, Danahay H, Howsham C, Hunt P, Paisley D, and Young A
- Subjects
- Amines pharmacology, Animals, Binding Sites, Bronchi drug effects, Epithelial Cells drug effects, Guinea Pigs, Humans, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Pyrazines pharmacology, Sodium Channel Blockers pharmacology, Amines chemistry, Epithelial Sodium Channel Blockers, Pyrazines chemistry, Sodium Channel Blockers chemistry
- 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 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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