Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides

Abstract

The soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxy-fatty acids, signaling molecules involved in numerous biologies. Toward finding novel inhibitors of sEH, a library of known drugs was tested for inhibition of sEH. We found that fulvestrant, an anticancer agent, is a potent (KI = 26 nM) competitive inhibitor of sEH. From this observation we found that alkyl-sulfoxides represent a new kind of pharmacophore for the inhibition of sEH.

Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation

“…More polar compounds, such as trans -4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid , that form additional bonds with the enzyme are less affected. Unfortunately, the relative low resolution ( ≈ 3 Å) of the available crystal structure of the human sEH ( 7,35,36 ) does not allow the effective modeling of such small changes.…”

Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

“…Based on the L-shaped hydrophobic pocket of sEH, lipophilic functional groups, such as adamantyl, biphenyl or halogens, can enhance the potency of urea-based inhibitors. Crystal structure of nonurea inhibitors, for example benzoxazole amide and fulvestrant, bound to sEH have been reported [ 61 , 62 ]. Xing and coworkers applied structure-based virtual screening to design combinatorial libraries to discover benzoxazole based novel and potent soluble epoxide hydrolase (sEH) inhibitors.…”

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

“…Dual function sEH inhibitors are available now, including those that also serve as stable EET analogues such as 8-HUDE (12-(3-hexylureido) dodec-8-enoic acid) [61,62], those that modulate peroxisome proliferator-activated receptors [63], and those that inhibit 5-lipoxygenase [64]. In addition, inhibitors with new pharmacophores are being developed [65–67], including urea-containing-pyrazoles that are dual inhibitors of sEH and cyclooxygenase-2 [68]. Furthermore, in addition to inhibiting sEH, N- cyclohexyl- N ′ - dodecanoic acid urea (CUDA) and AUDA are weak activators of peroxisome proliferator-activated receptor (PPAR) α [69].…”