Structure-pharmacokinetic-pharmacodynamic relationships of N-alkyl derivatives of the new antiepileptic drug valproyl glycinamide

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.