title: Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current IKs.
abstract: Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543, USA. saleem.ahmad@bms.com
authors.forename: Saleem
authors.initials: S
authors.lastname: Ahmad
authors.forename: Lidia
authors.initials: L
authors.lastname: Doweyko
authors.forename: Aaila
authors.initials: A
authors.lastname: Ashfaq
authors.forename: Francis N
authors.initials: FN
authors.lastname: Ferrara
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Bisaha
authors.forename: Joan B
authors.initials: JB
authors.lastname: Schmidt
authors.forename: John
authors.initials: J
authors.lastname: DiMarco
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Conder
authors.forename: Tonya
authors.initials: T
authors.lastname: Jenkins-West
authors.forename: Diane E
authors.initials: DE
authors.lastname: Normandin
authors.forename: Anita D
authors.initials: AD
authors.lastname: Russell
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Paul C
authors.initials: PC
authors.lastname: Levesque
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
authors.forename: Karnail S
authors.initials: KS
authors.lastname: Atwal
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000605:Amino Alcohols; D051668:Delayed Rectifier Potassium Channels; D007659:Ketones; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013764:Tetrahydronaphthalenes