Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs

Bioorg Med Chem Lett. 2021 Aug 15:46:128162. doi: 10.1016/j.bmcl.2021.128162. Epub 2021 May 29.

Abstract

In the United States, approximately one million individuals are hospitalized every year for arrhythmias, making arrhythmias one of the top causes of healthcare expenditures. Mexiletine is currently used as an antiarrhythmic drug but has limitations. The purpose of this work was to use normal and Long QT syndrome Type 3 (LQTS3) patient-derived human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify an analog of mexiletine with superior drug-like properties. Compared to racemic mexiletine, medicinal chemistry optimization of substituted racemic pyridyl phenyl mexiletine analogs resulted in a more potent sodium channel inhibitor with greater selectivity for the sodium over the potassium channel and for late over peak sodium current.

Keywords: Action potential duration; Early after depolarizations; Human induced pluripotent stem cell-derived cardiomyocytes; Long QT syndrome Type 3; Mexiletine analogs; Potassium channel; Sodium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiac Conduction System Disease / pathology*
  • Dose-Response Relationship, Drug
  • Humans
  • Induced Pluripotent Stem Cells / chemistry*
  • Long QT Syndrome / pathology*
  • Mexiletine / chemistry
  • Mexiletine / pharmacology*
  • Molecular Structure
  • Myocytes, Cardiac / pathology*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • NAV1.5 Voltage-Gated Sodium Channel
  • Pyridines
  • Mexiletine
  • pyridine

Supplementary concepts

  • Long QT syndrome type 3