Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA Hydrolase.

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 LTA hydrolase (LTAH) 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 LTAH provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTAH 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 . The effect of on the inflammatory lipid mediator profile characterizes dual sEH/LTAH inhibitors as an interesting option for future anti-inflammatory agent investigations.