Development of metabolically stable inhibitors of mammalian microsomal epoxide hydrolase

Christophe Morisseau, John W. Newman, Craig E. Wheelock, Thomas Hill, Dexter Morin, Alan R Buckpitt, Bruce D. Hammock

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 α to the terminal amide function and a thio-ether β 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 K1 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.

Original languageEnglish (US)
Pages (from-to)951-957
Number of pages7
JournalChemical Research in Toxicology
Volume21
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Epoxide Hydrolases
Amides
Liver Extracts
Eclampsia
Emphysema
Spontaneous Abortion
Xenobiotics
Polymorphism
Metabolism
Hydroxyl Radical
Ether
Carbon
Lung
Enzymes

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Morisseau, C., Newman, J. W., Wheelock, C. E., Hill, 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(4), 951-957. https://doi.org/10.1021/tx700446u

Development of metabolically stable inhibitors of mammalian microsomal epoxide hydrolase. / Morisseau, Christophe; Newman, John W.; Wheelock, Craig E.; Hill, Thomas; Morin, Dexter; Buckpitt, Alan R; Hammock, Bruce D.

In: Chemical Research in Toxicology, Vol. 21, No. 4, 04.2008, p. 951-957.

Research output: Contribution to journalArticle

Morisseau, C, Newman, JW, Wheelock, CE, Hill, T, Morin, D, Buckpitt, AR & Hammock, BD 2008, 'Development of metabolically stable inhibitors of mammalian microsomal epoxide hydrolase', Chemical Research in Toxicology, vol. 21, no. 4, pp. 951-957. https://doi.org/10.1021/tx700446u
Morisseau, Christophe ; Newman, John W. ; Wheelock, Craig E. ; Hill, Thomas ; Morin, Dexter ; Buckpitt, Alan R ; Hammock, Bruce D. / Development of metabolically stable inhibitors of mammalian microsomal epoxide hydrolase. In: Chemical Research in Toxicology. 2008 ; Vol. 21, No. 4. pp. 951-957.
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