Institute of Crystallography - CNR

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

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-?-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.

Archiv der Pharmazie (Weinh.)
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Milani Gualtiero1, Budriesi Roberta2, Tavazzani Elisa3, Cavalluzzi Maria Maddalena1, Mattioli Laura Beatrice2, Miniero Daniela Valeria4, Delre Pietro5,6, Belviso Benny Danilo6, Denegri Marco3, Cuocci Corrado6, Rotondo Natalie Paola1, De Palma Annalisa4, Gualdani Roberta7, Caliandroro Rocco , Mangiatordi6, Giuseppe Felice6, Kumawat Amit8, Camilloni Carlo8, Priori Silvia3,9,10, Lentini Giovanni1