Abstract
Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.
Highlights
Introduction iationsValproic acid (VPA, 2-propyl-pentanoic acid), is a fatty acid derivative of valeric acid naturally found in Valeriana officinalis [1,2]
Note—The change in anticonvulsant activity, teratogenicity and hepatotoxicity is mentioned with respect to valproic acid. * Since valpromide transforms into valproic acid in humans, there is no change in teratogenicity for valpromide; NA—not applicable, these compounds did not enter the clinical trials; N.D.—not determined; a : for acute migraine headache; b : for mania, schizoaffective disorder, manic type; c : drug tolerance study in health volunteers; d : for therapy-resistant patients with epilepsy
Emerging evidence demonstrates its use in other neurological disorders such as migraine, bipolar disorder and neuropathic pain
Summary
It is an eight-carbon molecule with the backbone of pentanoic acid and a propyl group attached to the second carbon. It has been reported that the carboxylic group of VPA that exists as an anion at physiological pH interacts with organic anion transporters (OATs) present on the foetal facing/basolateral plasma membrane of the placenta [23]. This interaction of VPA with OATs leads to VPA accumulation in foetus causing embryotoxicity [23]. Substantial side-effect, hepatotoxicity is primarily caused by metabolites of VPA (4-ene-VPA and 2,4-diene-VPA) [24,25,26,27]
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