2. Academic Validation
  3. Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes

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

  • J Med Chem. 2021 May 13;64(9):5384-5403. doi: 10.1021/acs.jmedchem.0c01545.
John R Cashman 1,  Daniel Ryan 1,  Wesley L McKeithan 2 3,  Karl Okolotowicz 1,  Jorge Gomez-Galeno 1,  Mark Johnson 1,  Kevin J Sampson 4,  Robert S Kass 4,  Arash Pezhouman 5,  Hrayr S Karagueuzian 5,  Mark Mercola 2 3
Affiliations

Affiliations

  • 1 Human BioMolecular Research Institute, San Diego, California 92121, United States.
  • 2 Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California 94305, United States.
  • 3 Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, California 92037, United States.
  • 4 Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, United States.
  • 5 Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States.
PMID: 33942619 DOI: 10.1021/acs.jmedchem.0c01545
Abstract

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".

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