title: Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: quaternary amines.
abstract: 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.
authors.affiliation: Novartis Institutes of Biomedical Research, Global Discovery Chemistry, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunt
authors.forename: Hazel C
authors.initials: HC
authors.lastname: Atherton-Watson
authors.forename: Jake
authors.initials: J
authors.lastname: Axford
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Collingwood
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Coote
authors.forename: Brian
authors.initials: B
authors.lastname: Cox
authors.forename: Sarah
authors.initials: S
authors.lastname: Czarnecki
authors.forename: Henry
authors.initials: H
authors.lastname: Danahay
authors.forename: Nick
authors.initials: N
authors.lastname: Devereux
authors.forename: Catherine
authors.initials: C
authors.lastname: Howsham
authors.forename: Peter
authors.initials: P
authors.lastname: Hunt
authors.forename: Victoria
authors.initials: V
authors.lastname: Paddock
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; D001980:Bronchi / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D026941:Sodium Channel Blockers