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United States Department of Agriculture

Agricultural Research Service

Title: Development of Metabolically Stable Inhibitors of Mammalian Microsomal Epoxide Hydrolase

Authors
item Morisseau, Christophe - UC DAVIS, ENTOMOLOGY
item Newman, John
item Wheelock, Craig - UC DAVIS, ENTOMOLOGY
item Hill, Iii, Thomas - UC DAVIS, MOLEC. BIOSCI.
item Morin, Dextor - UC DAVIS, MOLEC. BIOSCI.
item Buckpitt, Alan - UC DAVIS, MOLE. BIOSCI.
item Hammock, Bruce - UC DAVIS, ENTOMOLOGY

Submitted to: Chemical Research in Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 1, 2008
Publication Date: March 25, 2008
Citation: Morisseau, C., Newman, J.W., Wheelock, C.E., Hill, Iii, T., Morin, D., Buckpitt, A.R., Hammock, B.D. 2008. Development of metabolically stable inhibitors of mammalian microsomal epoxide hydrolase. Chemical Research in Toxicology. 21:951-957.

Interpretive Summary: The microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of ingested or inhaled compounds containing aromatic structures. Roles for this enzyme beyond these well known detoxification functions are poorly described to date. However, activity of this enzyme has been associated with a number of diseases, including emphysema, spontaneous abortion, eclampsia and several forms of cancer. To better understand the endogenous roles of this enzyme, new tools are needed. We recently demonstrated that fatty amides, such as elaidamide, represent a new class of mEH inhibitors. While these compounds are potent in vitro, they are quickly inactivated in vivo. To address these limitations, 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 on the carbon beside the terminal amide function and a thio-ether one carbon removed from this function increased mEH inhibition by an order of magnitude, while significantly reducing microsomal inactivation. Moreover, the addition of a hydroxyl group 9- to 10-carbons from the terminal amide function resulted in better inhibition potency without effecting microsomal stability. The best compound synthesized in this study, 2-nonylsulfanyl-propionamide, is a competitive inhibitor of mEH with a KI of 72 nM. This potent inhibitor significantly reduces mEH diol production in ex vivo lungs exposed to naphthalene, underlying the usefulness of the inhibitors described herein. These novel inhibitors appear to be valuable tools to investigate the physiological and biological roles of mEH.

Technical Abstract: 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 a to the terminal amide function and a thio-ether ß to this function increased mEH inhibition by an order of magnitude while significantly reducing microsomal inactivation. The addition of a hydroxyl group 9 to 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 KI 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.

Last Modified: 11/25/2014
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