Synthesis and cardiac electrophysiological activity of N-substituted-4-(1H-imidazol-1-yl)benzamides--new selective class III agents.
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.
Morgan
T K
TK
Medicinal Chemistry Department, Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Lis
R
R
Lumma
W C
WC
Nickisch
K
K
Wohl
R A
RA
Phillips
G B
GB
Gomez
R P
RP
Lampe
J W
JW
Di Meo
S V
SV
Marisca
A J
AJ
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
D000889:Anti-Arrhythmia Agents; D001549:Benzamides