（R）-N-（4'-取代）苄基 2-乙酰氨基-3-甲氧基丙酰胺的合成及抗惊厥活性。
Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides.
机构信息
Division of Medicinal Chemistry and Natural Products, University of North Carolina Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
出版信息
J Med Chem. 2010 Feb 11;53(3):1288-305. doi: 10.1021/jm901563p.
Abstract
The structure-activity relationship (SAR) for the N-benzyl group in the clinical antiepileptic agent (R)-lacosamide [(R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-3] has been explored. Forty-three compounds were prepared and then evaluated at the National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program for seizure protection in the maximal electroshock (MES) and subcutaneous Metrazol models. Comparing activities for two series of substituted aryl regioisomers (2', 3', 4') showed that 4'-modified derivatives had the highest activity. Significantly, structural latitude existed at the 4'-site. The SAR indicated that nonbulky 4'-substituted (R)-3 derivatives exhibited superb activity, independent of their electronic properties. Activities in the MES test of several compounds were comparable with or exceeded that of (R)-3 and surpassed the activities observed for the traditional antiepileptic agents phenytoin, phenobarbital, and valproate.
摘要
已探索了临床抗癫痫药物（R）-拉科酰胺[（R）-N-苄基 2-乙酰氨基-3-甲氧基丙酰胺，（R）-3]中 N-苄基的结构-活性关系（SAR）。合成了 43 种化合物，并在国立神经病学及中风研究院抗惊厥筛选计划中，通过最大电休克（MES）和皮下美替拉酮模型，评估了它们对癫痫保护的活性。比较两个系列取代芳基区域异构体（2'，3'，4'）的活性表明，4'-修饰的衍生物具有最高的活性。显著的是，4'-位存在结构适应性。SAR 表明，非庞大的 4'-取代（R）-3 衍生物表现出极好的活性，与其电子特性无关。几种化合物在 MES 测试中的活性与（R）-3 相当或超过（R）-3，并且超过了传统抗癫痫药物苯妥英、苯巴比妥和丙戊酸钠的活性。
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