Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA₄ Hydrolase

Abstract

Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure–activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA4H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA4H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA4H inhibitors as an interesting option for future anti-inflammatory agent investigations.

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

“…Thus, dual inhibition of LTA4H and sEH is likely to have superior effects in resolving inflammation due to accumulation of the anti-inflammatory EETs and blockage of the chemoattractant LTB4. Hiesinger et al developed amide derivatives with a benzothiazole core as a dual inhibitor of sEH and LTA4 hydrolase, thereby demonstrating another future route for development of anti-inflammatory agents [ 137 ]. Hefke et al deployed computer-aided fragment growing strategies to design amide based dual inhibitors of sEH and LTA4 hydrolase [ 138 ].…”

Mitochondria Are Potential Targets for the Development of New Drugs Against Neutrophilic Inflammation in Severe Pneumonia Including COVID-19

“…To promote the accumulation of EpFA, inhibitors of soluble epoxide hydrolase (sEH), which converts EpFA to less active metabolites, have been developed (Wagner et al, 2020). An excellent effect in the resolution of inflammation was achieved by the double inhibition of leukotriene A4 hydrolase and sEH (Hefke et al, 2020;Hiesinger et al, 2020). Dual 5-LOX/sEH inhibition significantly suppressed leukocyte activation (Meirer et al, 2016), and neutrophil infiltration (Garscha et al, 2017).…”

Systematic Assessment of Fragment Identification for Multitarget Drug Design

“…Our target choice covered the enzymes 5‐lipoxygenase (5‐LOX), soluble epoxide hydrolase (sEH) and leukotriene A4 hydrolase (LTA4H), as well as the nuclear receptors farnesoid X receptor (FXR) and retinoid X receptor (RXR). For several combinations of these proteins, sEH/5‐LOX, [11] sEH/LTA4H, [12] and sEH/FXR, [13] feasibility of a DML has been demonstrated. Despite their common feature of binding lipids and fatty acid mimetics, [14] the protein fold, catalysed reaction, as well as binding site shape and residues strongly differ in all five targets.…”