Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases
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 tightbinding inhibit...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1999-08, Vol.96 (16), p.8849-8854 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Morisseau, Christophe Goodrow, Marvin H. Dowdy, Deanna Zheng, Jiang Greene, Jessica F. Sanborn, James R. Hammock, Bruce D. |
| description | 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 tightbinding inhibitors with nanomolar Ki 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. |
| doi_str_mv | 10.1073/pnas.96.16.8849 |
| format | Article |
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Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tightbinding inhibitors with nanomolar Ki 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. 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| subjects | Animals Binding Sites Biological Sciences Carbamates Carbamates - chemical synthesis Carbamates - chemistry Carbamates - pharmacology Chemistry Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme substrates Enzymes Epoxide Hydrolases - antagonists & inhibitors Epoxide Hydrolases - chemistry Epoxy compounds Hammocks Humans Inhibitory concentration 50 Kinetics Mice Oxides Pesticides Recombinant Proteins - antagonists & inhibitors Structure-Activity Relationship Toxicity Urea - analogs & derivatives Urea - chemical synthesis Urea - chemistry Urea - pharmacology |
| title | Potent Urea and Carbamate Inhibitors of Soluble Epoxide Hydrolases |
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