Yin_2026_J.Med.Chem__

Bifunctional soluble epoxide hydrolase (sEH) represents an attractive therapeutic target for inflammation-associated disorders. Targeted protein degradation (TPD) offers new opportunities for targeting and blocking the enzymatic function of sEH, thereby ameliorating inflammation-related diseases. Herein, a diversity-oriented synthesis of 24 proteolysis-targeting chimeras (PROTACs) and 5 hydrophobic tag-targeted degraders (HyTTDs) was successfully facilitated by a Ugi-4CR reaction. Notably, the E3 ubiquitin ligase RNF126 and hydrophobic tag (HyT) ligands are delicately embedded in the degraders and exhibit moderate to good degradative activities toward sEH. After comprehensive biological screening, the PROTAC molecule 1d was found to have the highest degradation potency (DC(50) = 2.9 nM) and exhibited satisfactory degradative pharmacokinetic properties within 6 h, which further proved to significantly attenuate LPS-induced in vivo acute inflammation, highlighting its therapeutic utility.