Structure-pharmacokinetic-pharmacodynamic relationships of N-alkyl derivatives of the new antiepileptic drug valproyl glycinamide.
OBJECTIVE
The purpose of this study was to evaluate the structure-pharmacokinetic-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, neurotoxicity, and pharmacokinetics.


RESULTS
After i.p. administration to mice in the maximal electroshock seizure 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 (sc Met) model, M-VGD had a slightly lower ED50 than VGD (108 and 127 mg/kg, respectively). 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 derivatives studied, M-VGD had the best pharmacokinetic profile: the lowest clearance (5.4 L/h), the longest half-life (1.8 h), and the lowest liver-extraction ratio (14%). N,N-dialkylated VGD derivatives underwent two consecutive N-dealkylations, whereas N-alkylated derivatives underwent a single N-dealkylation process, yielding VGD as a major active metabolite.


CONCLUSIONS
M-VGD had the most favorable pharmacodynamic and pharmacokinetic 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. Therefore VGD rather than one of the investigated N-alkyl VGD derivatives should be considered for development as a new AED.
Spiegelstein
O
O
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Yagen
B
B
Bialer
M
M
D000478:Alkylation; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015195:Drug Design; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; C108894:TV 1901; D005998:Glycine