The structure-activity relationship of the 3-oxy site in the anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide.
Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure-activity relationship (SAR) for the compound's 3-oxy site. Placement of small nonpolar, nonbulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4'-benzylamide site in (R)-1 ( J. Med. Chem. 2010 , 53 , 1288 - 1305 ). Together, these results indicate that both the 3-oxy and 4'-benzylamide positions in (R)-1 can accommodate nonbulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model.
Morieux
Pierre
P
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
Salomé
Christophe
C
Park
Ki Duk
KD
Stables
James P
JP
Kohn
Harold
H
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology; D004597:Electroshock; D057927:Hydrophobic and Hydrophilic Interactions; D000078334:Lacosamide; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide