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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Antiepileptic Activity of Valproyl Hydroxamic Acid Derivatives (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 213-217 
    Details
    ISSN: 1573-904X
    Keywords: valproic acid ; valproyl hydroxamic acid derivatives ; pharmacokinetics ; antiepileptic activity ; structural requirements
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. Methods. The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anti-convulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. Results. Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid—VPA-HA, N-(l-hydroxyethyl)-valpromide—HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(l-methoxyethyl) valpromide and N-( 1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. Conclusions. In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012009012850
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  • 2
    Electronic Resource
    Electronic Resource
    Structure Activity Relationship of Human Microsomal Epoxide Hydrolase Inhibition by Amide and Acid Analogues of Valproic Acid (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 216-221 
    Details
    ISSN: 1573-904X
    Keywords: microsomal epoxide hydrolase inhibition ; valnoctamide ; valpromide analogues ; valproic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproicacid toward human microsomal epoxide hydrolase (mEH). Methods. mEH inhibition was evaluated in human liver microsomeswith 25 μ (S)-(+)-styrene oxide as the substrate. Inhibitory potencyexpressed as the median inhibitory concentration (IC50) was calculatedfrom the formation rate of the enzymatic product,(S)-(+)-1-phenyl-1,2-ethanediol. Results. Inhibitory potency was directly correlated with lipophilicityand became significant for amides with a minimum of eight carbonatoms. Branched eight-carbon amides were more potent inhibitors thantheir straight chain isomer, octanamide. N-substituted valproylamideanalogues had reduced or abolished inhibition potency with theexception of valproyl hydroxamic acid being a potent inhibitor. Inhibitionpotency was not stereoselective in two cases of chiral valpromideisomers. Valproyl glycinamide, a new antiepileptic drug currentlyundergoing phase II clinical trials and its major metabolite valproylglycine were weak mEH inhibitors. Acid isomers of valproic acid werenot potent mEH inhibitors. Conclusions. The structural requirements for valproylamide analoguesfor potent in vitro mEH inhibition are: an unsubstituted amide moiety;two saturated alkyl side chains; a minimum of eight carbons in themolecule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007577600088
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
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