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

Valproic acid (VPA) is one of the major antiepileptic drugs. However, its anticonvulsant potency is less than the other three major antiepileptic drugs. Furthermore, VPA causes two rare but severe side effects: teratogenicity and hepatotoxicity. We utilized pharmacokinetic considerations in designing various amide derivatives of VPA which are more potent as anticonvulsants than VPA and have the potential to be nonteratogenic and nonhepatotoxic. The following three groups of VPA derivatives were designed and evaluated: (1) Isomers of valpromide (VPD) in order to explore the structural requirements for metabolically stable VPD isomers. Two chiral amides, valnoctamide and propylisopropyl acetamide, have emerged from a stereospecific study as the optimal compounds; (2) Cyclic amide derivatives of VPD. N-Methyl 2,2,3, 3-tetramethylcyclopropane carboxamide (M-TMCD) was found to be the optimal compound 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 nonoxidative 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.