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Pharm Res. 2000 Feb;17(2):216-21.

Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid.

Author information

1
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.

Abstract

PURPOSE:

The purpose of this study was to evaluate the in vitro inhibitory potency of various amide analogues and derivatives of valproic acid toward human microsomal epoxide hydrolase (mEH).

METHODS:

mEH inhibition was evaluated in human liver microsomes with 25 microM (S)-(+)-styrene oxide as the substrate. Inhibitory potency expressed as the median inhibitory concentration (IC50) was calculated from the formation rate of the enzymatic product, (S)-(+)-1-phenyl-1,2-ethanediol.

RESULTS:

Inhibitory potency was directly correlated with lipophilicity and became significant for amides with a minimum of eight carbon atoms. Branched eight-carbon amides were more potent inhibitors than their straight chain isomer, octanamide. N-substituted valproylamide analogues had reduced or abolished inhibition potency with the exception of valproyl hydroxamic acid being a potent inhibitor. Inhibition potency was not stereoselective in two cases of chiral valpromide isomers. Valproyl glycinamide, a new antiepileptic drug currently undergoing phase II clinical trials and its major metabolite valproyl glycine were weak mEH inhibitors. Acid isomers of valproic acid were not potent mEH inhibitors.

CONCLUSIONS:

The structural requirements for valproylamide analogues for potent in vitro mEH inhibition are: an unsubstituted amide moiety; two saturated alkyl side chains; a minimum of eight carbons in the molecule.

PMID:
10751038
DOI:
10.1023/a:1007577600088
[Indexed for MEDLINE]

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