Synthesis and Toxicopharmacological Evaluation of m-Hydroxymexiletine, the First Metabolite of Mexiletine More Potent Than the Parent Compound on Voltage-Gated Sodium Channels

被引：30

作者：

Catalano, Alessia ^{[1
]}

Desaphy, Jean-Francois ^{[2
]}

Lentini, Giovanni ^{[1
]}

Carocci, Alessia ^{[1
]}

Di Mola, Antonia ^{[1
]}

Bruno, Claudio ^{[1
]}

Carbonara, Roberta ^{[2
]}

De Palma, Annalisa ^{[3
]}

Budriesi, Roberta ^{[4
]}

Ghelardini, Carla ^{[5
]}

Perrone, Maria Grazia ^{[1
]}

Colabufo, Nicola Antonio ^{[1
]}

Camerino, Diana Conte ^{[2
]}

Franchini, Carlo ^{[1
]}

机构：

[1] Univ Bari Aldo Moro, Dipartimento Farmacochim, I-70126 Bari, Italy

[2] Univ Bari Aldo Moro, Dipartimento Farmacobiol, Sez Farmacol, I-70126 Bari, Italy

[3] Univ Bari Aldo Moro, Dipartimento Farmacobiol, Sez Biochim, I-70126 Bari, Italy

[4] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy

[5] Univ Florence, Dipartimento Farmacol Preclin & Clin, I-50139 Florence, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 03期

关键词：

STEREOSPECIFIC SYNTHESIS; PHARMACOLOGY; DRUGS;

D O I：

10.1021/jm201197z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The first synthesis of m-hydroxymexiletine (MHM) has been accomplished. MHM displayed hNav1.5 sodium channel blocking activity, and tests indicate it to be similar to 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.

引用

页码：1418 / 1422

页数：5

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