title: Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.
abstract: Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.
authors.forename: J
authors.initials: J
authors.lastname: Lloyd
authors.forename: J B
authors.initials: JB
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Rovnyak
authors.forename: S
authors.initials: S
authors.lastname: Ahmad
authors.forename: K S
authors.initials: KS
authors.lastname: Atwal
authors.forename: S N
authors.initials: SN
authors.lastname: Bisaha
authors.forename: L M
authors.initials: LM
authors.lastname: Doweyko
authors.forename: P D
authors.initials: PD
authors.lastname: Stein
authors.forename: S C
authors.initials: SC
authors.lastname: Traeger
authors.forename: A
authors.initials: A
authors.lastname: Mathur
authors.forename: M L
authors.initials: ML
authors.lastname: Conder
authors.forename: J
authors.initials: J
authors.lastname: DiMarco
authors.forename: T W
authors.initials: TW
authors.lastname: Harper
authors.forename: T
authors.initials: T
authors.lastname: Jenkins-West
authors.forename: P C
authors.initials: PC
authors.lastname: Levesque
authors.forename: D E
authors.initials: DE
authors.lastname: Normandin
authors.forename: A D
authors.initials: AD
authors.lastname: Russell
authors.forename: R P
authors.initials: RP
authors.lastname: Serafino
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.forename: N J
authors.initials: NJ
authors.lastname: Lodge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: C439948:3-butyl-5-(4-(((2,2-dimethylcyclopent-1-yl)methyl)aminocarbonyl)phenyl)-1,2,4-oxadiazole; D001549:Benzamides; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496911:Kcnq1 protein, rat; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)