No abstract

Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N’-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.

Caulerpenyne (CYN) is a sesquiterpene from green algae with known inhibitory properties against soybean lipoxygenase. Here we introduce a detailed structure-activity study elucidating the inhibitory effects of CYN and a library of six synthetic CYN analogues on isolated human 5-lipoxygenase (5-LO) and cellular 5-LO in polymorphonuclear leukocytes. Essential structural elements are identified and a structurally simplified inhibitor is introduced. The modes of 5-LO inhibition by CYN and the synthetic inhibitors cannot be assigned to any of the known categories of lipoxygenase inhibitors. These compounds clearly interfere directly with 5-LO and represent rather small and flexible molecules, with unique structures among 5-LO inhibitors identified thus far.

No abstract

No abstract