title: Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines.
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.
authors.affiliation: Novartis Institutes of Biomedical Research, Global Discovery Chemistry, Horsham, West Sussex, United Kingdom. tom.hunt@novartis.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunt
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Atherton-Watson
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Collingwood
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Coote
authors.forename: Sarah
authors.initials: S
authors.lastname: Czarnecki
authors.forename: Henry
authors.initials: H
authors.lastname: Danahay
authors.forename: Catherine
authors.initials: C
authors.lastname: Howsham
authors.forename: Peter
authors.initials: P
authors.lastname: Hunt
authors.forename: Derek
authors.initials: D
authors.lastname: Paisley
authors.forename: Alice
authors.initials: A
authors.lastname: Young
mesh_terms: D000588:Amines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001980:Bronchi / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects; D062686:Epithelial Sodium Channel Blockers; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000588:Amines; D062686:Epithelial Sodium Channel Blockers; D011719:Pyrazines; D026941:Sodium Channel Blockers