Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase.
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.
Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
In-Hae
IH
Kim
Kosuke
K
Nishi
Takeo
T
Kasagami
Christophe
C
Morisseau
Jun-Yan
JY
Liu
Hsing-Ju
HJ
Tsai
Bruce D
BD
Hammock
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D012995:Solubility; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D004952:Esters; D004851:Epoxide Hydrolases