O. Spiegelstein et al., Structure-pharmacokinetic-pharmacodynamic relationships of N-alkyl derivatives of the new antiepileptic drug valproyl glycinamide, EPILEPSIA, 40(5), 1999, pp. 545-552
Purpose: The purpose of this study was to evaluate the structure-pharmacoki
netic-pharmacodynamic relationships of a series of N-alkyl and N,N-dialkyl
derivatives of the new antiepileptic drug (AED), valproyl glycinamide (VGD)
.
Methods: The following compounds were synthesized: N-methyl VGD (M-VGD), N,
N-dimethyl VGD, N-ethyl VGD, N,N-diethyl VGD (DE-VGD), and N,N-diisopropyl
VGD. These compounds were evaluated for anticonvulsant activity, neurotoxic
ity, and pharmacokinetics.
Results: After i.p. administration to mice in the maximal electroshock seiz
ure test (MES), DE-VGD had an ED50 value comparable to that of VGD (145 and
152 mg/kg, respectively), whereas in the subcutaneous metrazol test (se Me
t) model, M-VGD had a slightly lower ED, than VGD (108 and 127 mg/kg, respe
ctively). After oral administration to rats, M-VGD had an MES-ED50 similar
to that of VGD (75 and 73 mg/kg, respectively). Of the N-alkyl VGD derivati
ves studied, M-VGD had the best pharmacokinetic profile: the lowest clearan
ce (5.4 L/h), the longest half-life (1.8 h), and the lowest liver-extractio
n ratio (14%). N,N-dialkylated VGD derivatives underwent two consecutive N-
dealkylations, whereas N-alkylated derivatives underwent a single N-dealkyl
ation process, yielding VGD as a major active metabolite.
Conclusions: M-VGD had the most favorable pharmacodynamic and pharmacokinet
ic profile of the investigated N-alkyl VGD derivatives. VGD was found to be
a major active metabolite of M-VGD and to be less neurotoxic than M-VGD. T
herefore VGD rather than one of the investigated N-alkyl VGD derivatives sh
ould be considered for development as a new AED.