1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts.

Late sodium current () inhibitors are a new subclass of antiarrhythmic agents. To overcome the drawbacks, e.g., low efficacy and inhibition effect on K current, of the FDA-approved late inhibitor ranolazine, chain amide -, 1,4-disubstituted piperazin-2-ones -, and their derivatives - were successively designed, synthesized, and evaluated on the Na1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 μM. Among the new skeleton compounds, showed the highest efficacy (IC = 2.7 μM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice ( of 3.5 h, = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of in the treatments of arrhythmias related to the enhancement of late .