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.

Enantioselective synthesis and teratogenicity of propylisopropyl acetamide, a CNS-active chiral amide analogue of valproic acid

“…3,5 Since biological macromolecules are chiral entities and PID is a chiral mol-SYNTHESIS AND TERATOGENICITY OF PID ENANTIOMERS ecule, we found it important to synthesize the individual PID enantiomers and investigate their potential to induce congenital malformations in NMRI mice.…”

“…1), the primary amide of VPA is 3-15 times more potent than VPA in the above-mentioned models. [2][3][4] Propylisopropyl acetamide (PID) is a chiral isomer of VPD that contains one chiral carbon atom (Fig. 1), and has similar anticonvulsant potencies to VPD.…”

“…1), and has similar anticonvulsant potencies to VPD. 3,5 VPA is a potent teratogen that causes several forms of congenital malformations to infants of pregnant women treated with it during early embryogenesis. 6 VPA therapy is mainly associated with an increased risk of developing neural tube defects (NTDs).…”

Pharmacokinetics of Levetiracetam and Its Enantiomer (R)‐α‐ethyl‐2‐oxo‐pyrrolidine acetamide in Dogs

“…LEV might also be regarded as a heterocyclic analogue of VPD that contains the substitution of 2‐oxo‐pyrrolidine in the β‐position of the molecule. Thus, like aliphatic analogues of VPD (29,30), it undergoes metabolic hydrolysis to its corresponding acid PBA. The PK of REV has not been previously reported in any species, and this is also the first time that the PK of both enantiomers, LEV and REV, has been reported after i.v.…”

Anticonvulsant profile and teratogenicity of 3,3‐dimethylbutanoylurea: A potential for a second generation drug to valproic acid

“…The overall malformation rate is 11.1% in offspring of AED‐treated epileptic mothers, while it is 5.7% in the offspring of untreated epileptic mothers (Kaneko & Kondo, 1995). Many efforts have been made to design nonteratogenic VPA analogues and derivatives with enhanced anticonvulsant activity (Nau et al, 1991; Bialer et al, 1994; Isoherranen et al, 2003b; Bialer & Yagen, 2007). These urea derivatives displayed excellent broad‐spectrum anticonvulsant activity; however, at higher doses (335 mg/kg) they were teratogenic and embryotoxic (Shimshoni et al, 2007).…”