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Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides.


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.

SUBMITTER: Salome C 

PROVIDER: S-EPMC2818974 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Synthesis and anticonvulsant activities of (R)-N-(4'-substituted)benzyl 2-acetamido-3-methoxypropionamides.

Salomé Christophe C   Salomé-Grosjean Elise E   Park Ki Duk KD   Morieux Pierre P   Swendiman Robert R   DeMarco Erica E   Stables James P JP   Kohn Harold H  

Journal of medicinal chemistry 20100201 3


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 regioisomer  ...[more]

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