PHARMACOKINETICS AND ANTIEPILEPTIC ACTIVITY OF VALPROYL HYDROXAMIC ACID-DERIVATIVES

Purpose. To explore the utilization of seven novel hydroxamic acid der ivatives of valproic acid (VPA) as new antiepileptics. Methods. The st udy was carried out by investigating the pharmacokinetics of two activ e 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 hydroxa mic acid-VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpr omide, showed better anticonvulsant activity than VPA at the maximal e lectroshock (MES) test. The remaining four compounds, O-valproyl-VPA-H A, N-valproyl-O-valproyI-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 biotran sformed 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 H EV showed improved anticonvulsant activity over VPA because of their g reater intrinsic activity and not due to better pharmacokinetic charac teristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.