TY - JOUR
T1 - Can we develop improved derivatives of valproic acid?
AU - Bialer, Meir
AU - Haj-Yehia, Abdullah
AU - Badir, Khalil
AU - Hadad, Salim
PY - 1994/1
Y1 - 1994/1
N2 - 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 Iherapy. 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-pentenoatc 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.
AB - 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 Iherapy. 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-pentenoatc 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.
KW - 2-n-Propyl-2-pentenoic acid
KW - Drug evaluation
KW - Pharmacokinetics
KW - Structure-activity relationship
KW - Valproic acid
KW - Valpromide
UR - http://www.scopus.com/inward/record.url?scp=0028353534&partnerID=8YFLogxK
U2 - 10.1007/BF01870931
DO - 10.1007/BF01870931
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C2 - 8156045
AN - SCOPUS:0028353534
SN - 0928-1231
VL - 16
SP - 2
EP - 6
JO - International Journal of Clinical Pharmacy
JF - International Journal of Clinical Pharmacy
IS - 1
ER -