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

Autor: Milani G; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy., Budriesi R; Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Tavazzani E; ICS-Maugeri IRCCS, Pavia, Italy., Cavalluzzi MM; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy., Mattioli LB; Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum-University of Bologna, Bologna, Italy., Miniero DV; Department of Biosciences, Biotechnologies, and Environment, University Aldo Moro of Bari, Bari, Italy., Delre P; Chemistry Department, University of Bari Aldo Moro, Bari, Italy.; CNR-Institute of Crystallography, Bari, Italy., Belviso BD; CNR-Institute of Crystallography, Bari, Italy., Denegri M; ICS-Maugeri IRCCS, Pavia, Italy., Cuocci C; CNR-Institute of Crystallography, Bari, Italy., Rotondo NP; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy., De Palma A; Department of Biosciences, Biotechnologies, and Environment, University Aldo Moro of Bari, Bari, Italy., Gualdani R; Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium., Caliandro R; CNR-Institute of Crystallography, Bari, Italy., Mangiatordi GF; CNR-Institute of Crystallography, Bari, Italy., Kumawat A; Department of Biosciences, University of Milan, Milano, Italy., Camilloni C; Department of Biosciences, University of Milan, Milano, Italy., Priori S; ICS-Maugeri IRCCS, Pavia, Italy.; Molecular Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain., Lentini G; Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari, Italy.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2023 Oct; Vol. 356 (10), pp. e2300116. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1002/ardp.202300116
Abstrakt: 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.)
Databáze: MEDLINE
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