Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones as potent and selective I(Ks)-blocking class III antiarrhythmic agents.
Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones having various N-l substituents were identified as potent and selective blockers of the slowly activating cardiac delayed rectifier potassium current (I(Ks)). Compound 11 is the most potent I(Ks) channel blocker reported to date.
Butcher
John W
JW
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Liverton
Nigel J
NJ
Claremon
David A
DA
Freidinger
Roger M
RM
Jurkiewicz
Nancy K
NK
Lynch
Joseph J
JJ
Salata
Joseph J
JJ
Wang
Jixin
J
Dieckhaus
Christine M
CM
Slaughter
Donald E
DE
Vyas
Kamlesh
K
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D024642:Potassium Channels, Voltage-Gated; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D001569:Benzodiazepines