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

Late sodium current (I_Na) 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 I_Na inhibitor ranolazine, chain amide 6a-6q, 1,4-disubstituted piperazin-2-ones 7a-7s, and their derivatives 8a-8n were successively designed, synthesized, and evaluated in vitro on the Na_V1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 μM. Among the new skeleton compounds, 7d showed the highest efficacy (IC₅₀ = 2.7 μM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice (T_1/2 of 3.5 h, F = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late I_Na phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of 7d in the treatments of arrhythmias related to the enhancement of late I_Na.