Pharmacokinetics and antiepileptic activity of valproyl hydroxamic acid derivatives

Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid - VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(1-methoxyethyl) valpromide and N-(1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the 'active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant vaIproyl hydroxamic acid derivatives.