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

  • J Med Chem. 2025 Apr 24;68(8):8980-9013. doi: 10.1021/acs.jmedchem.5c00685.
Jing Ding  1 ,  Min-Zhen Zhu  2 ,  Xiao-Yu Du  3 ,  Si-Meng Liu  1 ,  Hao Wang  3 ,  Xing-Zhou Liu  1 ,  Wei-Song Xie  1 ,  Hong-Le Ma  1 ,  Yue Feng  3 ,  Xin-Hong Zhu  2 ,  Jian-Hua Liang  1
Affiliations
  • 1. Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China.
  • 2. Research Center for Brain Health, PazhouLab, Guangzhou 510330, China.
  • 3. College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
PMID: 40227865 DOI: 10.1021/acs.jmedchem.5c00685
Abstract

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, 77 (lab code: DJ-89; 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 TPPU and EC5026 (IC50: 44, 19 nM). Notably, 77 demonstrated additional interactions with sEH compared to TPPU, and uniquely enhanced anti-inflammatory factors, including EET levels and IL-10, a capability not observed with EC5026. Moreover, 77 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.

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