Substituted N-(Biphenyl-4鈥?yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels

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• 作者：Hyosung Lee ; Ki Duk Park ; Robert Torregrosa ; Xiao-Fang Yang ; Erik T. Dustrude ; Yuying Wang ; Sarah M. Wilson ; Cindy Barbosa ; Yucheng Xiao ; Theodore R. Cummins ; Rajesh Khanna ; Harold Kohn
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6165-6182
• 全文大小：1159K
• ISSN：1520-4804

文摘

We prepared 13 derivatives of N-(biphenyl-4鈥?yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound鈥檚 whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD₅₀/ED₅₀) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na⁺ channel slow inactivation and displayed frequency (use) inhibition of Na⁺ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.