• Patchliner

    Most versatile automated patch clamp system on the market
  • Patchliner

    In-house production and QC of consumables
  • Patchliner

    More than 10 years experience in assay design and support
  • Dynamite8

    Automated Dynamic Clamp
  • Patchliner

    All features & benefits of manual patch clamp

2021 - Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes

icon pl   Patchliner Publication in Journal of Medicinal Chemistry

Cashman J.R., Ryan D., McKeithan W.L., Okolotowicz K., Gomez-Galeno J., Johnson M., Sampson K.J., Kass R.S, Pezhouman A, Karagueuzian H.S., Mercola M.,

Journal of Medicinal Chemistry (2021) doi: 10.1021/acs.jmedchem.0c01545


Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (INaL) SCN5A mutations that prolongs cardiac action potential (AP) and enhances INaL current. Mexiletine inhibits INaL and shortens the QT interval in LQT3 patients. Above therapeutic doses, mexiletine prolongs the cardiac AP. We explored structure-activity relationships (SAR) for AP shortening and prolongation using dynamic medicinal chemistry and AP kinetics in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived LQT3 and healthy hiPSC-CMs, we resolved distinct SAR for AP shortening and prolongation effects in mexiletine analogues and synthesized new analogues with enhanced potency and selectivity for INaL. This resulted in compounds with decreased AP prolongation effects, increased metabolic stability, increased INaL selectivity, and decreased avidity for the potassium channel. This study highlights using hiPSC-CMs to guide medicinal chemistry and "drug development in a dish".

Download here

Back to Overview

We use cookies on our website. Some of them are essential for the operation of the site, while others help us to improve this site and the user experience (tracking cookies). You can decide for yourself whether you want to allow cookies or not. Please note that if you reject them, you may not be able to use all the functionalities of the site.