Discovery of Phenylacylpiperidine as Novel sEH Inhibitors through Scaffold Hopping of Natural Stilbene

Despite the development of soluble epoxide hydrolase (sEH) inhibitors as a promising therapeutic approach, no drug candidate has successfully progressed beyond clinical phase II, highlighting the need for a novel chemotype with improved in vivo potency, pharmacokinetics and safety. In this study, we discovered a phenylacetylpiperidine-based compound, <b>77</b> (lab code: <b>DJ-89</b>; IC₅₀: 0.51 nM), through strategic scaffold hopping from previously reported styrene-based sEH inhibitors. Resolving the cocrystal structure and mode-of-action studies revealed a distinct profile compared to well-known sEH inhibitors <b>TPPU</b> and <b>EC5026</b> (IC₅₀: 44, 19 nM). Notably, <b>77</b> demonstrated additional interactions with sEH compared to <b>TPPU</b>, and uniquely enhanced anti-inflammatory factors, including EET levels and IL-10, a capability not observed with <b>EC5026</b>. Moreover, <b>77</b> showed excellent pharmacokinetics and safety, positioning it as a promising candidate for treating both acute and chronic inflammatory diseases, including rheumatoid arthritis, leveraging phenylacylpiperidine scaffolds in sEH-targeted therapies.