Novartis Institutes of Biomedical Research, Global Discovery Chemistry, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
Bioorg Med Chem Lett. 2012 Jan 15;22(2):929-32. doi: 10.1016/j.bmcl.2011.12.016. Epub 2011 Dec 8.
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.
我们报告了一系列新型的人上皮钠离子通道（ENaC）阻断剂的鉴定，这些阻断剂在结构上与吡嗪甲酰胺胍化学型有区别，而吡嗪甲酰胺胍化学型存在于典型的 ENaC 阻断剂中，如阿米洛利。根据合理的设计假设，我们制备了一系列季铵盐，并评估了它们通过人支气管上皮细胞（HBEC）中 ENaC 阻断离子转运的能力。化合物 11 的 IC50 为 200nM，在豚鼠气管潜在差异（TPD）模型中具有功效，在 1 小时时，ENaC 阻断的 ED50 为 44μgkg-1。因此，吡嗪甲酰胺季铵盐代表了一类有前途的新型人 ENaC 阻断剂的首批实例。
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