Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes
作者： Hrayr S Karagueuzian , Wesley L McKeithan , Wesley L McKeithan , Kevin J Sampson , Arash Pezhouman
DOI: 10.1021/ACS.JMEDCHEM.0C01545
关键词: Mexiletine 、 Potassium channel 、 Pharmacology 、 Sodium channel 、 QT interval 、 Chemistry 、 Cardiac arrhythmia 、 Cardiac action potential 、 Heart disease 、 Long QT syndrome
摘要: Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a form of VA caused by sodium channel (INaL) SCN5A mutations that prolongs action potential (AP) and enhances INaL current. Mexiletine inhibits shortens the interval LQT3 patients. Above therapeutic doses, mexiletine AP. We explored structure-activity relationships (SAR) for AP shortening prolongation using dynamic medicinal chemistry kinetics human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived healthy hiPSC-CMs, we resolved distinct SAR effects analogues synthesized new with enhanced potency selectivity INaL. This resulted compounds decreased effects, increased metabolic stability, selectivity, avidity potassium channel. study highlights hiPSC-CMs to guide "drug development dish".
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