Key result
Meso mexiletine-derived urea 8 shows in vitro hERG opening without ex vivo cardiac or intestinal liability.
Why the study?
Long QT syndrome results in life-threatening arrhythmias with few drugs available for its management, particularly for LQT2 caused by mutations in the hERG potassium channel.
Does mexiletine-derived urea 8 stereoselectively modulate hERG channels and show safety in ex vivo models?
Does mexiletine-derived urea 8 stereoselectively modulate hERG channels and show safety in ex vivo models?
Answers are grounded in this paper and cite their sources.
The meso form of mexiletine-derived urea 8 demonstrates hERG opening activity without ex vivo cardiac or intestinal liability, suggesting potential for treating Long QT syndrome.
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.
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Milani et al. (2023) studied Long QT syndrome (LQTS). mexiletine-derived urea 8 was evaluated on hERG opening activity. The meso form of mexiletine-derived urea 8 demonstrated stereoselective hERG opening activity in vitro without cardiac or intestinal liability in ex vivo guinea pig models.
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