doi: 10.1016/j.bmc.2008.08.055.
Epub 2008 Aug 28.
Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives
Affiliations
- PMID: 18789868
- PMCID: PMC2701728
- DOI: 10.1016/j.bmc.2008.08.055
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Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives
Bioorg Med Chem.
.
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.
Figures
Three-step synthesis of (R)-lacosamide (1).
Synthesis of N-benzyl-(2R)-2-acetamido-3-oxysubstituted propionamide derivatives.
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