Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase
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- 作者：In-Hae Kim ; Kosuke Nishi ; Takeo Kasagami ; Christophe Morisseau ; Jun-Yan Liu ; Hsing-Ju Tsai ; Bruce D. Hammock
- 关键词：sEH ; soluble epoxide hydrolase ; EET ; epoxyeicosatrienoic acid ; EDCI ; 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide ; DMAP ; 4-dimethylaminopyridine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 September, 2012
- 年：2012
- 卷：22
- 期：18
- 页码：5889-5892
- 全文大小：946 K
文摘
Substituted ureas with a carboxylic acid ester as a secondary pharmacophore are potent soluble epoxide hydrolase (sEH) inhibitors. Although the ester substituent imparts better physical properties, such compounds are quickly metabolized to the corresponding less potent acids. Toward producing biologically active ester compounds, a series of esters were prepared and evaluated for potency on the human enzyme, stability in human liver microsomes, and physical properties. Modifications around the ester function enhanced in vitro metabolic stability of the ester inhibitors up to 32-fold without a decrease in inhibition potency. Further, several compounds had improved physical properties.