Synthesis, anticonvulsant activity, and neuropathic pain-attenuating activity of N-benzyl 2-amino-2-(hetero)aromatic acetamides

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• 作者：Pranjal K. Baruah^a ; ^&dagger ; ; Jason Dinsmore^a ; ^&dagger ; ; Amber M. King^a ; Christophe Salomé ; ^a ; Marc De Ryck^b ; Rafal Kaminski^b ; Laurent Provins^b ; Harold Kohn^a ; ^c ; ^{harold_kohn@unc.edu} ; ^{hkohn@email.unc.edu}
• 关键词：AED ; antiepileptic drug ; ASP ; Anticonvulsant Screening Program ; B ; P ; brain-to-plasma ; Cbz ; carboxybenzyl ; DBU ; 1 ; 8-diazabicycloundec-7-ene ; DIPEA ; N ; N-diisopropylethylamine ; DMTMM ; 4-(4 ; 6-dimethoxy-1 ; 3 ; 5-triazin-2-yl)-4-methylmorpholinium chloride ; ED50
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 June, 2012
• 卷：20
• 期：11
• 页码：3551-3564
• 文件大小：2940 K

摘要

N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2-acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain-attenuating activities in a mouse model.