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.
Highlights
The arachidonic acid (AA) cascade is one of the main regulatory pathways involved in the inflammatory response and associated diseases
A critical step in the design of a hybrid designed multi-target ligands (DMLs) is the careful choice of pharmacophores for the individual targets and the linker to interconnect them [11]
These considerations lead to the design of 1-(3-{5-(hydroxyureido)methyl-2-methoxyphenoxy}propyl)-3-[4(trifluoromethoxy)phenyl]urea 5 (KM55) as a potential dual soluble epoxide hydrolase (sEH)/5-LO inhibitor
Summary
The arachidonic acid (AA) cascade is one of the main regulatory pathways involved in the inflammatory response and associated diseases. The initial step of the AA cascade is the release of AA from membrane phospholipids by phospholipases [1]. Free AA is subsequently metabolized in three distinct branches of the AA cascade. The cyclooxygenase (COX) branch leads to the formation of various prostaglandins and thromboxane [2]. Leukotrienes and lipoxins are formed by the enzymes of the lipoxygenase (LO) branch [3]. Oxidation of AA by cytochrome P450 (CYP) enzymes results in the biosynthesis of epoxyeicosatrienoic acids (EETs), which are subsequently degraded to dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH) [4]. Almost all key enzymes of the AA cascade are of interest in pharmaceutical research, only COX inhibitors, one 5-LO inhibitor, and antagonists of cysteinyl leukotriene receptors and thromboxane receptors are in clinical use
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
