4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: a novel class III antiarrhythmic agents.
A series of 4,5-dihydro-3-[2-(methanesulfonamidophenyl)ethyl]-1-phenyl- 1H-2,4-benzodiazepines has been identified as potential antiarrhythmic agents that interact at the delayed rectifier myocardial potassium channels (IKr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Langendorff heart preparations. Structure-activity relationship (SAR) studies based upon prolongation of ERP indicate that placement of the sulfonamido group is important for potent activity in this model. Furthermore, methanesulfonamido has enhanced activity over its ethyl or trifluoromethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesulfonamidophenyl to the benzodiazepine. Further incremental improvements in activity were noted when the 1-phenyl ring was substituted with a variety of substituents. Chirality of the compounds of interest in this series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all possess high selectivity for blockade of potassium current in hearts relative to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may represent potential new class III agents, but with the potential liability of myocardial IKr blockers.
Johnson
R E
RE
Department of Medicinal Chemistry, Sterling Winthrop Research, Collegeville, Pennsylvania 19426, USA.
Silver
P J
PJ
Becker
R
R
Birsner
N C
NC
Bohnet
E A
EA
Briggs
G M
GM
Busacca
C A
CA
Canniff
P
P
Carabateas
P M
PM
Chadwick
C C
CC
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D015222:Sodium Channels / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D015222:Sodium Channels; D001569:Benzodiazepines