title: Discovery and synthesis of tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers.
abstract: A novel class of tetrahydroindolone-derived semicarbazones has been discovered as potent Kv1.5 blockers. In in vitro studies, several compounds exhibited very good potency for blockade of Kv1.5. Compound 8i showed good selectivity for blockade of Kv1.5 vs hERG and L-type calcium channels. In an anesthetized pig model, compounds 8i and 10c increased atrial ERP about 28%, 18%, respectively, in the right atrium without affecting ventricular ERP.
authors.affiliation: Procter & Gamble Pharmaceuticals, Mason Business Center, 8700 Mason-Montgomery Road, Mason, OH 45040, USA. wu.s.3@pg.com
authors.forename: Shengde
authors.initials: S
authors.lastname: Wu
authors.forename: Andrew
authors.initials: A
authors.lastname: Fluxe
authors.forename: John M
authors.initials: JM
authors.lastname: Janusz
authors.forename: James B
authors.initials: JB
authors.lastname: Sheffer
authors.forename: Greg
authors.initials: G
authors.lastname: Browning
authors.forename: Benjamin
authors.initials: B
authors.lastname: Blass
authors.forename: Keith
authors.initials: K
authors.lastname: Cobum
authors.forename: Richard
authors.initials: R
authors.lastname: Hedges
authors.forename: Michael
authors.initials: M
authors.lastname: Murawsky
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: Gina M
authors.initials: GM
authors.lastname: Fadayel
authors.forename: Michelle
authors.initials: M
authors.lastname: Hare
authors.forename: Laurent
authors.initials: L
authors.lastname: Djandjighian
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000494:pharmacology; D019054:Evoked Potentials, Motor / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D009483:Neuropsychological Tests; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D012664:Semicarbazones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D020746:Calcium Channels, L-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D012664:Semicarbazones