title: Synthesis and cardiac electrophysiological activity of N-substituted-4-(1H-imidazol-1-yl)benzamides--new selective class III agents.
abstract: The synthesis and cardiac electrophysiological activity of 18 N-substituted imidazolylbenzamides or benzene-sulfonamides are described. Compounds 6a,d,f-k and 11 exhibited potency in the in vitro Purkinje fiber assay comparable to that of N-[2-(diethylamino)ethyl]-4- [(methylsulfonyl)amino]benzamide (1, sematilide), a potent selective class III agent which is undergoing clinical trials. These data indicate that the 1H-imidazol-1-yl moiety is a viable replacement for the methylsulfonylamino group for producing class III electrophysiological activity in the N-substituted benzamide series. N-[2-(Diethylamino)ethyl]-4-(1H-imidazol-1-yl)benzamide dihydrochloride (6a) was further studied in two in vivo models of reentrant arrhythmias and showed potency and efficacy comparable to those of 1.
authors.affiliation: Medicinal Chemistry Department, Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
authors.forename: T K
authors.initials: TK
authors.lastname: Morgan
authors.forename: R
authors.initials: R
authors.lastname: Lis
authors.forename: W C
authors.initials: WC
authors.lastname: Lumma
authors.forename: K
authors.initials: K
authors.lastname: Nickisch
authors.forename: R A
authors.initials: RA
authors.lastname: Wohl
authors.forename: G B
authors.initials: GB
authors.lastname: Phillips
authors.forename: R P
authors.initials: RP
authors.lastname: Gomez
authors.forename: J W
authors.initials: JW
authors.lastname: Lampe
authors.forename: S V
authors.initials: SV
authors.lastname: Di Meo
authors.forename: A J
authors.initials: AJ
authors.lastname: Marisca
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis*; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004594:Electrophysiology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides