Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 25, Issue 8, Pages 1705-1708Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.02.076
Keywords
Soluble epoxide hydrolase; Inhibitor; Epoxyeicosatrienoic acids; Three substituted cyclopropane; Conformational regulation
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We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values). (C) 2015 Elsevier Ltd. All rights reserved.
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