Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 3, Pages 1163-1175Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.12.027
Keywords
Substituted oxyoxalamides; Human soluble epoxide hydrolase; Inhibitors
Funding
- Hyundai Pharm Research Grant [HOB-024]
- NIEHS [R01 ES002710]
- Japan Society for the Promotion of Science [23710042]
- Grants-in-Aid for Scientific Research [23710042] Funding Source: KAKEN
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We explored both structure-activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors. When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives. In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility. In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility. The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.
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