title: 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.
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Salomé
authors.forename: Elise
authors.initials: E
authors.lastname: Salomé-Grosjean
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Pierre
authors.initials: P
authors.lastname: Morieux
authors.forename: Robert
authors.initials: R
authors.lastname: Swendiman
authors.forename: Erica
authors.initials: E
authors.lastname: DeMarco
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004597:Electroshock; D006624:Hippocampus / Q000187:drug effects; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D003292:Convulsants; D012694:Serine; D010433:Pentylenetetrazole