SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 6-HETEROCYCLIC-SUBSTITUTED PURINES AS INACTIVATION MODIFIERS OF CARDIAC SODIUM-CHANNELS

Purine-based analogs of SDZ 211-500 (5) were prepared and evaluated as inactivation modifiers of guinea pig or human cardiac sodium (Na) cha nnels expressed in Xenopus oocytes. Substances which remove or slow th e Na channel inactivation process in cardiac tissue are anticipated to prolong the effective refractory period and increase inotropy and thu s have potential utility as antiarrhythmic agents. Heterocyclic substi tution at the 6-position of the purine ring resulted in compounds with increased Na activity and potency, with 5-membered heterocycles being optimal. Only minor modifications to the benzhydrylpiperazine side ch ain were tolerated. Selected compounds which delayed the inactivation of Na channels were found to increase refractoriness and contractility in a rabbit Langendorff heart model, consistent with the cellular mec hanism. Activity in both the oocyte and rabbit heart assays was specif ic to the S enantiomers. Preliminary in vivo activity has been demonst rated following intravenous infusion. The most promising compound on t he basis of in vitro data is the formylpyrrole (S)-74, which is 25-fol d more potent than DPI 201-106 (1) in the human heart Na channel assay .