Abstract
The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be ∼2-fold more potent than the parent mexiletine and to have more favorable toxicological properties than mexiletine. Thus, MHM and possible related prodrugs might be studied as agents for the treatment of arrhythmias, neuropathic pain, and myotonias in substitution of mexiletine (metabolite switch), which has turned out to be tainted with common toxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Anti-Arrhythmia Agents / chemical synthesis*
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Anti-Arrhythmia Agents / metabolism
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Anti-Arrhythmia Agents / toxicity
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Aorta / drug effects
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Aorta / physiology
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Ataxia / chemically induced
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Blood-Brain Barrier / metabolism
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Caco-2 Cells
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Guinea Pigs
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HEK293 Cells
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Heart / drug effects
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Heart / physiology
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Heart Rate / drug effects
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Humans
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Ion Channel Gating
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Mexiletine / analogs & derivatives*
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Mexiletine / chemical synthesis
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Mexiletine / metabolism*
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Mexiletine / toxicity
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Mice
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NAV1.5 Voltage-Gated Sodium Channel
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Permeability
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Sodium Channels / physiology*
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Stereoisomerism
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Vasodilator Agents / chemical synthesis
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Vasodilator Agents / toxicity
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Anti-Arrhythmia Agents
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NAV1.5 Voltage-Gated Sodium Channel
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SCN5A protein, human
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Scn5a protein, mouse
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Sodium Channels
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Vasodilator Agents
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3-hydroxymexiletine
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Mexiletine