Peptidyl-urea based inhibitors of soluble epoxide hydrolases.
We prepared a series of amino acid derived cyclohexyl and adamantyl ureas and tested them as inhibitors of the human soluble epoxide hydrolase, and obtained very potent compounds (K(I)=15nM) that are >10-fold more soluble than previously described sEH inhibitors. While our lead compound 2 showed low apparent bioavailability in dogs and rats, this series of compounds revealed that sEH inhibitor structures could accept large groups that could lead to better orally available drugs.
Morisseau
Christophe
C
Department of Entomology and UCD Cancer Center, University of California, Davis, CA 95616, USA.
Newman
John W
JW
Tsai
Hsing-Ju
HJ
Baecker
Preston A
PA
Hammock
Bruce D
BD
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D010455:Peptides; D014508:Urea; D004851:Epoxide Hydrolases