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.

hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation / 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; Lentini, Giovanni. - In: ARCHIV DER PHARMAZIE. - ISSN 1521-4184. - ELETTRONICO. - 356:10(2023), pp. e2300116-1. [10.1002/ardp.202300116]

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

Budriesi, Roberta;Mattioli, Laura Beatrice;
2023

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.
2023
hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation / 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; Lentini, Giovanni. - In: ARCHIV DER PHARMAZIE. - ISSN 1521-4184. - ELETTRONICO. - 356:10(2023), pp. e2300116-1. [10.1002/ardp.202300116]
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; Lentini, Giovanni
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/943993
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