Pharmacokinetic considerations in the design of better and safer new antiepileptic drugs

Valproic acid (VPA) is one of the major antiepileptic drugs. However, its a nticonvulsant potency is less than the other three major antiepileptic drug s. Furthermore, VPA causes two rare but severe side effects: teratogenicity and hepatotoxicity. We utilized pharmacokinetic considerations in designin g various amide derivatives of VPA which are more potent as anticonvulsants than VPA and have the potential to be nonteratogenic and nonhepatotoxic. T he following three groups of VPA derivatives were designed and evaluated: ( 1) Isomers of valpromide (VPD) in order to explore the structural requireme nts for metabolically stable VPD isomers. Two chiral amides, valnoctamide a nd propylisopropyl acetamide, have emerged from a stereospecific study as t he optimal compounds; (2) Cyclic amide derivatives of VPD. N-Methyl 2,2,3,3 -tetramethylcyclopropane carboxamide (M-TMCD) was found to be the optimal c ompound in this series. M-TMCD is a stable achiral VPD analogue acid which is nonteratogenic. Since M-TMCD contains four methyl substituents it cannot form a metabolite with a terminal double bond, and thus has the potential to be a nonhepatotoxic compound; (3) Conjugation products of VPA and gamma- amino butyric acid (GABA) or glycine. N-valproyl glycinamide (VGD) emerged as the best compound out of this group and is currently undergoing phase II clinical trials. VGD is mainly metabolized to N-valproyl glycine by a nono xidative hydrolytic metabolic pathway. It did not operate as chemical drug delivery systems of VPA and glycine or GABA, but acted rather as a drug on its own. (C) 1999 Elsevier Science B.V. All rights reserved.