Potent urea and carbamate inhibitors of soluble epoxide hydrolases

Christophe Morisseau, Marvin H. Goodrow, Deanna Dowdy, Jiang Zheng, Jessica F. Greene, James R. Sanborn, Bruce D. Hammock

Research output: Contribution to journalArticle

200 Scopus citations

Abstract

The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tight-binding inhibitors with nanomolar K(i) values interacted stoichiometrically with the homogenous recombinant murine and human sEHs. These inhibitors enhance cytotoxicity of trans- stilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome. These potent inhibitors may be valuable tools for testing hypotheses of involvement of diol and epoxide lipids in chemical mediation in vitro or in vivo systems.

Original languageEnglish (US)
Pages (from-to)8849-8854
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number16
DOIs
StatePublished - Aug 3 1999

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ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Morisseau, C., Goodrow, M. H., Dowdy, D., Zheng, J., Greene, J. F., Sanborn, J. R., & Hammock, B. D. (1999). Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proceedings of the National Academy of Sciences of the United States of America, 96(16), 8849-8854. https://doi.org/10.1073/pnas.96.16.8849