Primary Amino Acid Derivatives: Substitution of the 4鈥?N鈥?Benzylamide Site in (R)-N鈥?Benzyl 2-Amino-3-methylbutanamide, (R)-N鈥?Benzyl 2-Amino-3,3-dimethylbutanamide,

详细信息    查看全文

• 作者：Amber M. King ; Christophe Salom茅 ; Elise Salom茅-Grosjean ; 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：6417-6431
• 全文大小：1288K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Recently, we reported that select N鈥?benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N鈥?benzyl 2-amino acetamides (MES ED₅₀ = 13鈥?1 mg/kg) exceeded those of phenobarbital (ED₅₀ = 22 mg/kg). Two additional studies defining the structure鈥揳ctivity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N鈥?benzyl 2-amino-3-methylbutanamide and (R)-N鈥?benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4鈥?N鈥?benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4鈥?N鈥?benzylamide site of (R)-N鈥?benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (4-fold) increase in activity (ED₅₀ = 8.9 mg/kg), a value that surpassed phenytoin (ED₅₀ = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.