2. Academic Validation
  3. Development of potent inhibitors of the human microsomal epoxide hydrolase

Development of potent inhibitors of the human microsomal epoxide hydrolase

  • Eur J Med Chem. 2020 May 1;193:112206. doi: 10.1016/j.ejmech.2020.112206.
Bogdan Barnych 1,  Nalin Singh 1,  Sophie Negrel 1,  Yue Zhang 2,  Damien Magis 1,  Capucine Roux 1,  Xiude Hua 3,  Zhewen Ding 1,  Christophe Morisseau 1,  Dean J Tantillo 2,  Justin B Siegel 4,  Bruce D Hammock 5
Affiliations

Affiliations

  • 1 Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States.
  • 2 Department of Chemistry, University of California Davis, Davis, CA, 95616, United States.
  • 3 Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States; College of Plant Protection, Nanjing Agricultural University, Nanjing, 210095, China.
  • 4 Department of Chemistry, University of California Davis, Davis, CA, 95616, United States; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, 95616, United States; Genome Center, University of California Davis, Davis, CA, 95616, United States.
  • 5 Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, United States. Electronic address: bdhammock@ucdavis.edu.
PMID: 32203787 DOI: 10.1016/j.ejmech.2020.112206
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.

Keywords

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

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