Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/16568
Title
hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation.
Author(s)
Milani, Gualtiero | Budriesi, Roberta | Tavazzani, Elisa | Cavalluzzi, Maria Maddalena | Mattioli, Laura Beatrice | Miniero, Daniela Valeria | Delre, Pietro | Belviso, Benny Danilo | Denegri, Marco | Cuocci, Corrado | Rotondo, Natalie Paola | De Palma, Annalisa | Gualdani, Roberta | Caliandro, Rocco | Mangiatordi, Giuseppe Felice | Kumawat, Amit | Camilloni, Carlo | Priori, Silvia G. CNIC | Lentini, Giovanni
Date issued
2023-10
Citation
Arch Pharm (Weinheim). 2023 Oct;356(10):e2300116.
Language
Inglés
Document type
journal article
Abstract
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.
MESH
Mexiletine | Long QT Syndrome | Humans | Animals | Guinea Pigs | Molecular Docking Simulation | Urea | Structure-Activity Relationship | Potassium Channels
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