CAN WE DEVELOP IMPROVED DERIVATIVES OF VALPROIC ACID

Valproic acid is one of the major antiepileptic drugs, In animal model s, valproate showed less anticonvulsant potency than the other three e stablished antiepileptic drugs: phenobarbital, phenytoin and carbamaze pine. In addition, two major side-effects, teratogenicity and hepatoto xicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial nee d to develop improved derivatives of valproate. This paper analyses th ree kinds of valproate derivatives: valpromide,the primary amide of va lproate, and its analogues; monoester prodrugs of valproate and an act ive metabolite of valproate, 2-n-propyl-2-pentenoate, The comparative evaluation was carried but by pharmacokinetic and pharmacodynamic anal yses in animals. From the data accumulated so far, we can conclude tha t 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not u ndergo amide-acid biotransformation and preferably is not an epoxide h ydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.