Key result
Optimized mexiletine analog compound 22 shows ~85% greater AUC and no CNS toxicity vs mexiletine.
Why the study?
Mexiletine has potential liabilities such as potassium channel inhibition and adverse reactions, so the authors tested whether re-engineering it via dynamic medicinal chemistry could produce a candidate with greater efficacy and less toxicity.
Do synthetic deuterated analogs of mexiletine improve efficacy and reduce toxicity compared to mexiletine in LQTS3 models?
Do synthetic deuterated analogs of mexiletine improve efficacy and reduce toxicity compared to mexiletine in LQTS3 models?
Deuterated mexiletine analogs show improved pharmacokinetic profiles and reduced CNS toxicity compared to mexiletine in preclinical models, representing a potential new treatment for LQTS3.
May support analog development for LQTS3; leaves open human translation from animal data alone.
Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome‐3 (LQTS3) is caused by mutations in the Na v 1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re‐engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient‐derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on‐target) and detrimental effects (off‐target) of mexiletine and synthetic analogs, respectively. The approach combined “drug discovery” and "hit to lead” refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22 . Compared to mexiletine, compound 22 showed a 1.85‐fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P‐450, as previously shown, and by the flavin‐containing monooxygenase (FMO). Deuterated‐ 22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.
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Gomez‐Galeno et al. (2021) studied Long QT syndrome-3 (LQTS3). Compound 22 and deuterated-22 (mexiletine analogs) vs. Mexiletine was evaluated on Pharmacokinetics, toxicity, and metabolism (1.85-fold greater AUC). Compared to mexiletine, the optimized analog compound 22 showed a 1.85-fold greater AUC and no detectable CNS toxicity at 100 mg/kg, with deuterated-22 showing decreased metabolism.
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