Structure‐Pharmacokinetic‐Pharmacodynamic Relationships of yV‐Alkyl Derivatives of the New Antiepileptic Drug Valproyl Glycinamide

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Abstract
Summary:Purpose: The purpose of this study was to evaluate the structure‐phartnacokinetie‐pharmacodynamic relationships of a series ofN‐alkyl andN,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), andN,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 ED50value 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 ED50than VGD (108 and 127 mg/kg, respectively). After oral administration to rats, M‐VGD had an MES‐ED50similar to that of VGD (75 and 73 mg/kg, respectively). Of theN‐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 consecutiveN‐dealkylations, whereasN‐alkylated derivatives underwent a singleN‐dealkylation process, yielding VGD as a major active metabolite.Conclusions: M‐VGD had the most favorable pharmacodynamic and pharmacokinetic profile of the investigatedN‐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 /V‐alkyl VGD derivatives should be considered for development as a new AED.