hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation.

Publisher: Wiley-VCH Verlag GmbH & Co. KGaA Country of Publication: Germany NLM ID: 0330167 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-4184 (Electronic) Linking ISSN: 03656233 NLM ISO Abbreviation: Arch Pharm (Weinheim) Subsets: MEDLINE

Publication: <2005->: Weinheim Germany : Wiley-VCH Verlag GmbH & Co. KGaA
Original Publication: Weinheim, Verlag Chemie GmbH.

Mexiletine*/pharmacology ; Long QT Syndrome*/genetics ; Long QT Syndrome*/therapy; Humans ; Animals ; Guinea Pigs ; Molecular Docking Simulation ; Urea ; Structure-Activity Relationship ; Potassium Channels/metabolism

Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS.
(© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

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# GGP19134 Fondazione Telethon-Italy

Keywords: hERG channels; long QT syndrome; mexiletine; molecular docking; ureas

1U511HHV4Z (Mexiletine)
8W8T17847W (Urea)
0 (Potassium Channels)

Date Created: 20230717 Date Completed: 20231006 Latest Revision: 20231006

20240829

10.1002/ardp.202300116

37460390