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

详细信息	查看全文 | 推荐本文 |

• 作者：Thomas Hunt^a ; ^{tom.hunt@novartis.com} ; Hazel C. Atherton-Watson^b ; Stephen P. Collingwood^a ; Kevin J. Coote^b ; Sarah Czarnecki^b ; Henry Danahay^b ; Catherine Howsham^a ; Peter Hunt^a ; Derek Paisley^b ; Alice Young^b
• 关键词：ENaC blocker ; Epithelial sodium channel ; Quaternary amine ; Cystic fibrosis ; Amiloride
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April, 2012
• 卷：22
• 期：8
• 页码：2877-2879
• 文件大小：615 K

摘要

We report the synthesis and biological evaluation of a series of novel 伪-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 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED₅₀ of 1 渭g kg^鈭? 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.