Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5889-92. doi: 10.1016/j.bmcl.2012.07.074. Epub 2012 Aug 2.
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.
用羧酸酯替代脲作为第二药效团的取代基是强效的可溶性环氧化物水解酶（sEH）抑制剂。尽管酯取代基赋予了更好的物理性质，但这些化合物很快会代谢为效力较低的相应酸。为了产生具有生物活性的酯化合物，我们合成了一系列酯类化合物，并评估了它们对人源酶的效力、在人肝微粒体中的稳定性以及物理性质。酯功能的修饰使酯抑制剂的体外代谢稳定性提高了 32 倍，而抑制效力没有降低。此外，一些化合物的物理性质得到了改善。
