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Lookup NU author(s): Dr Cinzia Bordoni,
Daniel Lopez Fernandez,
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.
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
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
Notes: Chapter 19.
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