Development of potent inhibitors of the human microsomal epoxide hydrolase.

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 IC 50 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. Image 1 • Designed 2-alkylthio acetamide inhibitors of microsomal epoxide hydrolase, low nanomolar IC 50 (0.94–11 nM). • Novel series, 2 orders of magnitude more potent than previous amines, amides and ureas (IC 50 ≥ 480 nM). • Best inhibitors possess amide with bulky α-substituent and, 3–4 bonds away, phenyl ring with lipophilic meta groups. • Docking simulations validate findings, favorable active site interactions (amide H-bonding, π–π stacking). [ABSTRACT FROM AUTHOR]