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Cardiac Ion Channel Inhibition

Lookup NU author(s): Dr Cinzia Bordoni, Daniel Brough, Gemma Davison, James Hunter, Daniel Lopez Fernandez, Kate McAdam, Duncan MillerORCiD, Pasquale Morese, Alexia Papaioannou, Melanie Uguen, Professor Mike Waring


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© The Royal Society of Chemistry 2021.Interaction with cardiac ion channels can potentially result in severe or even fatal cardiac side effects. The most prominent of cardiac channels, human ether-a-go-go-related gene (hERG), voltage-gated sodium channel 1.5 (NaV1.5) and voltage-gated calcium channel 1.2 (CaV1.2), which traffic major ion currents shaping cardiac action potential, are recognized as primary counter-screen targets. These channels possess relatively large inner pores with multiple binding sites and can accommodate a variety of structurally diverse ligands. This chapter provides a short overview of in vitro approaches in preclinical cardiotoxicity screening, gives a summary of available structural data and pharmacophore models for hERG, NaV1.5 and CaV1.2 as well as discusses medicinal chemistry strategies that were successfully applied to mitigate cardiotoxicity risk. The major highlighted approaches are lipophilicity reduction, basicity reduction and removal or modification of (hetero)aromatic substituents. The strategies are illustrated by multiple examples from recent literature.

Publication metadata

Author(s): Bordoni C, Brough DJ, Davison G, Hunter JH, Lopez-Fernandez JD, McAdam K, Miller DC, Morese PA, Papaioannou A, Uguen M, Ratcliffe P, Sitnikov N, Waring MJ

Editor(s): Schnider P

Publication type: Book Chapter

Publication status: Published

Book Title: The Medicinal Chemist’s Guide to Solving ADMET Challenges

Year: 2021

Pages: 403-492

Print publication date: 27/08/2021

Acceptance date: 02/04/2020

Series Title: RSC Drug Discovery Series

Publisher: Royal Society of Chemistry

Place Published: Cambridge


DOI: 10.1039/9781788016414-00403

Notes: Chapter 19.

Library holdings: Search Newcastle University Library for this item

ISBN: 9781788012270