N-Aryl-2,6-dimethylbenzamides, a New Generation of Tocainide Analogues as Blockers of Skeletal Muscle Voltage-Gated Sodium Channels

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• 作者：Marilena Muraglia ; Michela De Bellis ; Alessia Catalano ; Alessia Carocci ; Carlo Franchini ; Antonio Carrieri ; Cecilia Fortugno ; Carlo Bertucci ; Jean-Fran莽ois Desaphy ; Annamaria De Luca ; Diana Conte Camerino ; Filomena Corbo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2589-2600
• 全文大小：435K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

On the basis of a 3D-QSAR study, a new generation of tocainide analogues were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. Data obtained by screening new compounds by means of Hille-Campbell Vaseline gap voltage-clamp recordings showed that the elongation of the alkyl chain and the introduction of lipophilic and sterically hindered groups on the amino function enhance both potency and use-dependent block. The results provide additional indications about the structural requirement of pharmacophores for further increasing potency and state-dependent block and allowed us to identify a new tocainide analogue (6f) with a favorable pharmacodynamic profile to be proposed as a valid candidate for studies aimed at evaluating its usefulness in the treatment of myotonias.