Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes.

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Medicinal Chemistry

Background:

• Ventricular arrhythmia (VA) is linked to acquired or congenital heart disease.
• Long QT syndrome type-3 (LQT3), a congenital VA, stems from SCN5A mutations affecting the cardiac sodium channel (I_NaL), prolonging cardiac action potential (AP).
• Mexiletine, while effective at therapeutic doses for LQT3, can prolong AP at higher concentrations.

Purpose of the Study:

• To investigate structure-activity relationships (SAR) for AP shortening and prolongation effects of mexiletine analogues.
• To synthesize novel analogues with enhanced potency and selectivity for I_NaL.
• To develop safer LQT3 therapeutics using a
• drug development in a dish
• approach.

Main Methods:

• Utilized dynamic medicinal chemistry and AP kinetics.
• Employed human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), including patient-derived LQT3 models and healthy controls.
• Synthesized and characterized novel mexiletine analogues.

Main Results:

• Resolved distinct SAR for AP shortening and prolongation of mexiletine analogues.
• Developed new analogues with improved potency and selectivity for I_NaL.
• Achieved compounds with reduced AP prolongation, enhanced metabolic stability, and decreased off-target potassium channel avidity.

Conclusions:

• hiPSC-CMs are valuable tools for guiding medicinal chemistry in drug development.
• Novel mexiletine analogues demonstrate potential for safer and more effective LQT3 treatment.
• This study advances the concept of
• drug development in a dish
• for cardiac channelopathies.