title: Synthesis and toxicopharmacological evaluation of m-hydroxymexiletine, the first metabolite of mexiletine more potent than the parent compound on voltage-gated sodium channels.
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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari "Aldo Moro", Via E. Orabona, 4, 70126 Bari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Desaphy
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lentini
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Mola
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.forename: Roberta
authors.initials: R
authors.lastname: Carbonara
authors.forename: Annalisa
authors.initials: A
authors.lastname: De Palma
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Diana
authors.initials: D
authors.lastname: Conte Camerino
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001259:Ataxia / Q000139:chemically induced; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D006168:Guinea Pigs; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010539:Permeability; D015222:Sodium Channels / Q000502:physiology*; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D014665:Vasodilator Agents; C069734:3-hydroxymexiletine; D008801:Mexiletine