SULFONAMIDOPHENYL)-1-PHENYL-1H-2,4-BENZODIAZEPINES - A NOVEL CLASS-III ANTIARRHYTHMIC AGENTS

A series of anesulfonamidophenyl)ethyl]-1H-2,4-benzodiazepines has bee n identified as potential antiarrhythmic agents that interact at the d elayed rectifier myocardial potassium channels (I-Kr) and prolong the ventricular effective refractory period (ERP) in rabbit isolated Lange ndorff heart preparations. Structure-activity relationship (SAR) studi es based upon prolongation of ERP indicate that placement of the sulfo namido group is important for potent activity in this model. Furthermo re, methanesulfonamido has enhanced activity over its ethyl or trifluo romethyl analogs. Slightly greater activity was observed in compounds that had a heteroatom in the ethyl bridge that connects the methanesul fonamidophenyl 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 thi s series does not appear to influence activity in this model. Several of these compounds were chosen for advanced evaluation, and all posses s high selectivity for blockade of potassium current in hearts relativ e to other ion channels. In addition, these compounds prolong cardiac refractoriness in dogs following oral dosing. Thus, these agents may r epresent potential new class III agents, but with the potential liabil ity of myocardial I-Kr blockers.