Abstract
Heart disease is one of the top causes of healthcare expenses in the United States. Lethal ventricular cardiac arrhythmia can arise in acquired or congenital heart disease. Long QT syndrome type 3 (LQT3) is a congenital form of ventricular arrhythmia caused by mutations in the cardiac sodium channel SCN5A. Mexiletine is a Class 1 antiarrhythmic drug that inhibits INa-L and shortens the QT interval in LQT3 patients. However, slightly above therapeutic doses, Mexiletine prolongs the cardiac action potential. Mexiletine was reengineered in an iterative process called dynamic medicinal chemistry to explore structure activity relationships (SAR) for AP shortening and prolongation of AP kinetics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Certain newly synthesized Mexiletine analogs showed enhanced potency and selectivity for INa-L and low proarrhythmic liability and less central nervous system toxicity than the parent compound. In an aged animal model of oxidative stress that produces early after depolarization (EAD) formation and other arrhythmogenic effects, certain Mexiletine analogs examined were observed to reverse arrhythmogenic effects. Further modification using selected deuterated Mexiletine analogs showed that improvement to pharmacologic and pharmaceutical properties can be achieved. In conclusion, studies highlighted the utility of using hiPSC-cardiomyocytes to guide medicinal chemistry and obtain new chemotypes for “cardiovascular drug discovery in a dish”.
Keywords
Human induced pluripotent stem cells (hiPSCs), Ventricular tachycardia (VT), Ventricular fibrillation (VF), Action potential (AP), Long QT syndrome type 3 (LQT3)