Ciaglia_2025_Eur.J.Med.Chem_302_118338

Multitarget approaches are highly effective strategies for treating acute and chronic inflammatory diseases. In this field, the dual inhibition of 5-lipoxygenase-activating protein (FLAP) and soluble epoxide hydrolase (sEH) offers the advantage of reducing the production of diverse pro-inflammatory lipid mediators (LMs) while preserving pro-resolving mediator levels. However, this approach is underexplored in medicinal chemistry, given the limited number of existing dual inhibitors. Here, we present the rational design of the adamantylureido-benzylamide aniline 6, which features in vitro FLAP/sEH inhibitory activity. An accurate investigation about the crucial interactions between our synthesized derivatives and 5LOX, FLAP and sEH binding sites, led us to shed light on structural requirements differentiating among the three targets. Lipidomic profiling following 6in vivo administration highlighted the reduction of 5-LOX/FLAP- and sEH-derived LMs, resulting in a favourable redistribution of LMs in agreement with the inhibition of its molecular targets.