Design Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase

摘要

The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor >KM55 was rationally designed and synthesized. >KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of >KM55 in human whole blood and endothelial cells was investigated. >KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. >KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.