4,5-DIHYDRO-1-PHENYL-1H-2,4-BENZODIAZEPINES - NOVEL ANTIARRHYTHMIC AGENTS

A series of 4,5-dihydro-1-phenyl-1H-2,4-benzodiazepines has been ident ified as potential antiarrhythmic agents that interact with sodium and potassium channels and prolong the ventricular effective refractory p eriod (ERP) in anesthetized guinea pigs. Concomitant displacement of r adiolabeled bactrachotoxin from site II in Na+ channels and of radiola beled dofetilide from delayed rectifier K+ channels was evident with a ll members of this chemical series at a concentration of 10 muM. Struc ture-activity relationship (SAR) studies using a paced guinea pig mode l to assess prolongation of the ERP indicated that methyl or ethyl at the 1-position had little effect on activity, while larger groups caus ed a diminution of activity. Compounds with substituents at either the 3- or 4-position that increased lipophilicity generally were more pot ent; however, too many lipophilic substituents simultaneously at posit ions 1, 3, and 4 resulted in less active compounds. Substituents on ei ther aromatic ring had little influence on activity, and phenyl at the 5-position resulted in a significant reduction in antiarrhythmic acti vity. When two sets of enantiomerically pure compounds were tested in the guinea pig, chirality was shown to be important for activity of 8, where the (R)-enantiomer was the more active, but not in the case of 15, where the enantiomers were equiactive. Several compounds in this s eries increased the threshold for vertricular fibrillation and refract oriness in myocardially-infarcted anesthetized cata and delayed the on set of aconitine-induced arrhythmias in anesthetized guinea pigs follo wing intravenous dosing. Moreover, these compounds possessed oral anti arrhythmic activity in conscious myocardially-infarcted dogs. Compound R-15 has been advanced for further biological and toxicological evalu ations.