hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation
Articolo
Data di Pubblicazione:
2023
Citazione:
hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation / G. Milani, R. Budriesi, E. Tavazzani, M.M. Cavalluzzi, L.B. Mattioli, D.V. Miniero, P. Delre, B.D. Belviso, M. Denegri, C. Cuocci, N.P. Rotondo, A. De Palma, R. Gualdani, R. Caliandro, G.F. Mangiatordi, A. Kumawat, C. Camilloni, S. Priori, G. Lentini. - In: ARCHIV DER PHARMAZIE. - ISSN 0365-6233. - (2023), pp. e2300116.1-e2300116.17. [Epub ahead of print] [10.1002/ardp.202300116]
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-a-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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
hERG channels; long QT syndrome; mexiletine; molecular docking; ureas
Elenco autori:
G. Milani, R. Budriesi, E. Tavazzani, M.M. Cavalluzzi, L.B. Mattioli, D.V. Miniero, P. Delre, B.D. Belviso, M. Denegri, C. Cuocci, N.P. Rotondo, A. De Palma, R. Gualdani, R. Caliandro, G.F. Mangiatordi, A. Kumawat, C. Camilloni, S. Priori, G. Lentini
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