title: Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives.
abstract: Lacosamide has been submitted for regulatory approval in the United States and Europe for the treatment of epilepsy. Previous synthetic methods did not permit the elaboration of the structure-activity relationship (SAR) for the 3-oxy site in lacosamide. We report an expedient five-step stereospecific synthesis for N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide analogs beginning with D-serine methyl ester. The procedure incorporated alkyl (e.g. methyl, primary, secondary, and tertiary) and aryl groups at this position. The SAR for the 3-oxy site showed maximal activity in animal seizure models for small 3-alkoxy substituents.
authors.affiliation: Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Campus Box 7360, Chapel Hill, NC 27599-7360, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morieux
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 / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D000078334:Lacosamide; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide
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