Searching for new antiarrhythmic agents: Evaluation of meta-hydroxymexiletine enantiomers

• meta-Hydroxymexiletine (MHM) is a metabolite of mexiletine more potent than mexiletine.
• MHM enantiomers were synthesized.
• (R)-MHM exhibited high antiarrhythmic activity.
• (R)-MHM represents a valid candidate for a chiral switch.

Mexiletine is a very well-known class IB antiarrhythmic drug, whose enantiomers differ in both pharmacodynamic and pharmacokinetic properties, the (R)-isomer being the eutomer on experimental arrhythmias and in binding studies on cardiac voltage-gated sodium channels. meta-Hydroxymexiletine (MHM) is a minor metabolite of mexiletine, which has demonstrated to be more potent than the parent compound. Herein we report the synthesis and biological evaluation of MHM enantiomers for their potential antiarrhythmic activity. The same stereoselectivity pattern observed for mexiletine was found for MHM: the (R)-enantiomer of MHM was the eutomer on ac-arrhythmia also showing a negative inotropism higher than the one displayed by mexiletine and, at the same time, a decreased vasorelaxant activity on guinea-pig left atrium and guinea-pig ileum longitudinal smooth muscle.

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