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

Abstract

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.

Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics

“…Several other dual acting bifunctional small molecules that include sEH inhibitor activity have been developed (Proschak et al, 2017). These dual-acting molecules combine sEH inhibition with c-Raf inhibition, fatty acid amide hydrolase inhibition, 5-LOX inhibition, farnesoid X receptor agonism, or PPAR agonism (Meirer, et al, 2016; Proschak et al, 2017; Schmidt et al, 2017; Temml et al, 2017). In addition, a few sEH inhibitors such as AUDA have EET agonistic activity and EET analogs have sEH inhibitor activity that varies from none to nanomolar IC 50 sEH inhibitor activity (Falck et al, 2014; Olearczyk et al, 2006).…”

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

“…Other sEH/5-LO dual inhibitors include fragment-based development of 2-aminothiazole derivatives [ 142 ]. Meirer et al developed a dual 5-LO/sEH inhibitor KM55 which significantly inhibits the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation [ 143 ]. Dual inhibitors for sEH and fatty acid amide hydrolase (FAAH) have been shown to synergize responses to inflammatory and neuropathic pain [ 144 , 145 ] Dual inhibitors focused on sEH have sought to leverage the role of targets that are implicated in regulation of inflammation.…”

Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain

“…In conclusion, this study presents a proof of concept for the sEH/PDE4 dual inhibitor approach on analgesia and therefore adds to the concept of previous poly-pharmacological tools targeting sEH in combination with other enzymes. 16,18,31 Nevertheless, several experiments will have to be performed in the future to clarify the therapeutic improvements of the dual inhibitor. Further in vivo experiments, including ferret or other emetic models are necessary to define the side effects caused by the dual inhibitor in comparison to classical PDEIs.…”