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.