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 _V 1.5-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 (IC ₅₀ = 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 .