Development of metabolically stable inhibitors of Mammalian microsomal epoxide hydrolase.
The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of xenobiotics such as polyaromatic toxicants. Additionally, polymorphism studies have underlined a potential role of this enzyme in relation to a number of diseases, such as emphysema, spontaneous abortion, eclampsia, and several forms of cancer. We recently demonstrated that fatty amides, such as elaidamide, represent a new class of potent inhibitors of mEH. While these compounds are very active on recombinant mEH in vitro, they are quickly inactivated in liver extracts reducing their value in vivo. We investigated the effect of structural changes on mEH inhibition potency and microsomal stability. Results obtained indicate that the presence of a small alkyl group alpha to the terminal amide function and a thio-ether beta to this function increased mEH inhibition by an order of magnitude while significantly reducing microsomal inactivation. The addition of a hydroxyl group 9-10 carbons from the terminal amide function resulted in better inhibition potency without improving microsomal stability. The best compound obtained, 2-nonylsulfanyl-propionamide, is a competitive inhibitor of mEH with a K I of 72 nM. Furthermore, this new inhibitor significantly reduces mEH diol production in ex vivo lungs exposed to naphthalene, underlying the usefulness of the inhibitors described herein. These novel inhibitors could be valuable tools to investigate the physiological and biological roles of mEH.
Morisseau
Christophe
C
Department of Entomology, U. C. Cancer Center, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
Newman
John W
JW
Wheelock
Craig E
CE
Hill Iii
Thomas
T
Morin
Dexter
D
Buckpitt
Alan R
AR
Hammock
Bruce D
BD
D000818:Animals; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
D009281:Naphthalenes; D011994:Recombinant Proteins; C031721:naphthalene; D004851:Epoxide Hydrolases