Chemistry and biotransformation

Abstract

Since the serendipitous discovery of the anticonvulsant activity of valproic acid (VPA) by Munier in 1963, and its introduction to the clinic in 1967, the study of the metabolic fate and diverse pharmacological activity of VPA metabolites have progressively continued for three decades. Up to fifty VPA metabolites were identified by 1987 [1], with a few of these demonstrating significant biological activity. As a result, VPA metabolites have been studied in detail not only with respect to their antiepileptic potential ([2] and see below), but also as model compounds to characterize the structural requirements for induction of teratogenic or hepatotoxic effects (see Radatz and Nau, this volume) and also to elucidate the biochemical nature of novel pathways of biotransformation, e.g. cytochrome P450-mediated desaturation and (ω-2)-hydroxylation [3]. In light of the need for rational drug-design of new efficacious antiepileptic drugs having minimal sideeffects and free of the undesired interactions with other antiepileptic agents, structure-activity relationship studies of VPA analogues and metabolites have played a pivotal role towards the development of new antiepileptic agents [4–7]. The current chapter describes the chemistry and structure-activity relationships (SAR) of VPA analogues and related metabolites, followed by an overview on the metabolic pathways involved in VPA biotransformation.KeywordsValproic AcidAcyl GlucuronideMedium Chain Length Fatty AcidOfvalproic AcidDipropylacetic AcidThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.