Synthesis and anticonvulsant activity of N-benzyloxycarbonyl amino acid prodrugs of phenytoin

Glycine, which has weak anticonvulsant properties, has been shown to potentiate the activity of several antiepileptic drugs but not phenytoin. Recently, studies have shown that N-(benzyloxycarbonyl)glycine (Z-glycine) antagonized seizures more than glycine in addition to possessing activity in the maximal electroshock test, a convulsive model in which glycine is inactive. In the present study eaters of 3-hydroxymethylphenytoin, a phenytoin prodrug, and Z-glycine as well as the homologous N-(benzyloxycarbonyl)-omega-amino acids, Z-beta-alanine and Z-gamma-aminobutyric acid (Z-GABA), were prepared and tested for their anticonvulsant and acute neurotoxic activities. The phenytoin prodrugs were obtained by esterification of bis(2-oxo-3-oxazolidinyl)-phosphinic acid chloride-mediated esterification of 3-hydroxymethylphenytoin with the respective N-benzyloxycarbonyl-protected amino acid. The Z-glycine-phenytoin ester was the most active anticonvulsant derivative. Compared with phenytoin the compound exhibited a decreased median effective dose (ED50) in the MES test and an increased median toxic dose (TD50), resulting in an significantly improved protective index expressed as the ratio between TD50 and ED50. The present data suggest that covalent binding of phenytoin to Z-glycine results in an improved pharmacological profile of the drug.