Defining the Structural Parameters That Confer Anticonvulsant Activity by the Site-by-Site Modification of (R)-N鈥?Benzyl 2-Amino-3-methylbutanamide

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• 作者：Amber M. King ; Marc De Ryck ; Rafal Kaminski ; Anne Valade ; James P. Stables ; Harold Kohn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6432-6442
• 全文大小：1014K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Primary amino acid derivatives (PAADs) (N鈥?benzyl 2-substituted 2-amino acetamides) are structurally related to functionalized amino acids (FAAs) (N鈥?benzyl 2-substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model, and the reported structure鈥揳ctivity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4鈥?N鈥?benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogues of (R)-N鈥?benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s).