Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin.
Scriba GK, Lambert DM
Department of Pharmaceutical Chemistry, University of Munster, Germany.
scriba@uni-muenster.de
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 esters 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.
PMID: 10411214, UI: 99337021