title: Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold.
abstract: TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50=16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay.
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flaherty
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA.
authors.forename: Denise S
authors.initials: DS
authors.lastname: Simpson
authors.affiliation: Johns Hopkins University, School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Miller
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA.
authors.forename: Brooks E
authors.initials: BE
authors.lastname: Maki
authors.affiliation: Johns Hopkins University, School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zou
authors.affiliation: Johns Hopkins University, School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Aubé
authors.affiliation: Johns Hopkins University, School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center, Baltimore, MD 21205, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: University of Kansas Specialized Chemistry Center, Lawrence, KS 66047, USA. Electronic address: jengolden@ku.edu.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; C498655:KCNK9 protein, human; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3
keywords: Bis-amide; KCNK3; Selective potassium channel inhibitor; TASK1