- 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,Salomé, Christophe,Park, Ki Duk,Stables, James P.,Kohn, Harold
-
body text
p. 5716 - 5726
(2010/10/03)
-
- Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives
-
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.
- Morieux, Pierre,Stables, James P.,Kohn, Harold
-
experimental part
p. 8968 - 8975
(2009/04/06)
-