title: Can we develop improved derivatives of valproic acid?
abstract: Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Bialer
authors.forename: A
authors.initials: A
authors.lastname: Haj-Yehia
authors.forename: K
authors.initials: K
authors.lastname: Badir
authors.forename: S
authors.initials: S
authors.lastname: Hadad
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001711:Biotransformation; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy*; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D011355:Prodrugs; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; C004651:dipropylacetamide