| 4,5-Dihydro-3-(methanesulfonamidophenyl)-1-phenyl-1H-2,4-benzodiazepines: a novel class III antiarrhythmic agents. | |
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MedLine Citation:
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PMID: 7629795 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 38 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1995 Jul |
Date Detail:
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Created Date: 1995-09-01 Completed Date: 1995-09-01 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2551-6 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, Sterling Winthrop Research, Collegeville, Pennsylvania 19426, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Arrhythmia Agents / chemistry, metabolism, pharmacology* Benzodiazepines / chemistry, metabolism, pharmacology* Calcium Channels / metabolism Dogs Humans Infant Magnetic Resonance Spectroscopy Male Myocardial Contraction / drug effects Rabbits Radioligand Assay Sodium Channels / metabolism Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Anti-Arrhythmia Agents; 0/Calcium Channels; 0/Sodium Channels; 12794-10-4/Benzodiazepines |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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