title: Design and synthesis of novel isoquinoline-3-nitriles as orally bioavailable Kv1.5 antagonists for the treatment of atrial fibrillation.
abstract: Novel 3-cyanoisoquinoline Kv1.5 antagonists have been prepared and evaluated in in vitro and in vivo assays for inhibition of the Kv1.5 potassium channel and its associated cardiac potassium current, IKur. Structural modifications of isoquinolinone lead 1 afforded compounds with excellent potency, selectivity, and oral bioavailability.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA. bwesley_trotter@merck.com
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Kett
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Gary L
authors.initials: GL
authors.lastname: Stump
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kiss
authors.forename: Jixin
authors.initials: J
authors.lastname: Wang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Spencer
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Beshore
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dinsmore
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001682:Biological Availability; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D051666:Kv1.5 Potassium Channel; D009570:Nitriles