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Badir, Khalil; Haj‐Yehia, Abdullah; Vree, T. B.; Kleijn, Eppo van der; Bialer, Meir

doi:10.1023/a:1015854118110

Cited by 15 publications

(2 citation statements)

References 12 publications

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“…Introduction of a double bond at C-2 (2-ene-VPA) led to improved anticonvulsant activity . In addition to the modifications of the aliphatic moiety of VPA, several valproic acid ester derivatives have been tested .…”

Section: Introductionmentioning

confidence: 99%

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Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives

2004

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Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity.

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Section: Introductionmentioning

confidence: 99%

“…In addition to the modifications of the aliphatic moiety of VPA, several valproic acid ester derivatives have been tested . Recently, several ester derivatives of VPA with sugar alcohols have been synthesized and some were found to be active as anticonvulsants .…”

Section: Introductionmentioning

confidence: 99%

Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives

2004

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Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid

Hadad

Vree

Kleijn

et al. 1993

Biopharm & Drug Disp

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The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divalproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.

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Prodrug Approaches for Drug Delivery to the Brain

Anderson

Prodrugs

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Cited by 15 publications

References 12 publications

Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives

Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid

Prodrug Approaches for Drug Delivery to the Brain

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