Development of potent inhibitors of the human microsomal epoxide hydrolase

Bogdan Barnych, Nalin Singh, Sophie Negrel, Yue Zhang, Damien Magis, Capucine Roux, Xiude Hua, Zhewen Ding, Christophe Morisseau, Dean J. Tantillo, Justin B. Siegel, Bruce D. Hammock

Research output: Contribution to journalArticle

Abstract

Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units.

Original languageEnglish (US)
Article number112206
JournalEuropean Journal of Medicinal Chemistry
Volume193
DOIs
StatePublished - May 1 2020

Keywords

  • 2-Alkylthio acetamide series
  • Amides
  • Benzyl-thio
  • Enzyme inhibitors
  • Microsomal epoxide hydrolase
  • Molecular docking

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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    Barnych, B., Singh, N., Negrel, S., Zhang, Y., Magis, D., Roux, C., Hua, X., Ding, Z., Morisseau, C., Tantillo, D. J., Siegel, J. B., & Hammock, B. D. (2020). Development of potent inhibitors of the human microsomal epoxide hydrolase. European Journal of Medicinal Chemistry, 193, [112206]. https://doi.org/10.1016/j.ejmech.2020.112206