Document Detail

4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: a novel class III antiarrhythmic agents.
MedLine Citation:
PMID:  7629795     Owner:  NLM     Status:  MEDLINE    
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.
R E Johnson; P J Silver; R Becker; N C Birsner; E A Bohnet; G M Briggs; C A Busacca; P Canniff; P M Carabateas; C C Chadwick
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  38     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1995 Jul 
Date Detail:
Created Date:  1995-09-01     Completed Date:  1995-09-01     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2551-6     Citation Subset:  IM    
Department of Medicinal Chemistry, Sterling Winthrop Research, Collegeville, Pennsylvania 19426, USA.
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MeSH Terms
Anti-Arrhythmia Agents / chemistry,  metabolism,  pharmacology*
Benzodiazepines / chemistry,  metabolism,  pharmacology*
Calcium Channels / metabolism
Magnetic Resonance Spectroscopy
Myocardial Contraction / drug effects
Radioligand Assay
Sodium Channels / metabolism
Structure-Activity Relationship
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Calcium Channels; 0/Sodium Channels; 12794-10-4/Benzodiazepines

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