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For example, long QT syndrome\u20103 (LQTS3) is caused by mutations in the Na<jats:sub>v<\/jats:sub>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\u2010engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient\u2010derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on\u2010target) and detrimental effects (off\u2010target) of mexiletine and synthetic analogs, respectively. The approach combined \u201cdrug discovery\u201d and \"hit to lead\u201d refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound <jats:bold>22<\/jats:bold>. Compared to mexiletine, compound <jats:bold>22<\/jats:bold> showed a 1.85\u2010fold greater AUC and no detectable CNS toxicity at 100\u00a0mg\/kg. In vitro hepatic metabolism studies showed that <jats:bold>22<\/jats:bold> was metabolized via cytochrome P\u2010450, as previously shown, and by the flavin\u2010containing monooxygenase (FMO). Deuterated\u2010<jats:bold>22<\/jats:bold> showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.<\/jats:p>","DOI":"10.1002\/prp2.828","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T05:28:09Z","timestamp":1627622889000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs"],"prefix":"10.1002","volume":"9","author":[{"given":"Jorge","family":"Gomez\u2010Galeno","sequence":"first","affiliation":[{"name":"Human BioMolecular Research Institute San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Okolotowicz","sequence":"additional","affiliation":[{"name":"Department of Medicine Cardiovascular Institute Stanford University Stanford CA 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