Structure activity relationship of human microsomal epoxide hydrolase inhibition by amide and acid analogues of valproic acid.
OBJECTIVE
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.
Spiegelstein
O
O
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Kroetz
D L
DL
Levy
R H
RH
Yagen
B
B
Hurst
S I
SI
Levi
M
M
Haj-Yehia
A
A
Bialer
M
M
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005026:Ethylene Glycols / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008099:Liver / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000577:Amides; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D005026:Ethylene Glycols; C031474:styrene glycol; C045179:valnoctamide; D014635:Valproic Acid; D004851:Epoxide Hydrolases; C004651:dipropylacetamide