2. Academic Validation
  3. Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors

Discovery of a novel lead characterized by a stilbene-extended scaffold against sepsis as soluble epoxide hydrolase inhibitors

  • Eur J Med Chem. 2024 Jan 3:266:116113. doi: 10.1016/j.ejmech.2023.116113.
Zi-Qiang Feng 1,  Jing Ding 1,  Min-Zhen Zhu 2,  Wei-Song Xie 1,  Rui-Chen Liu 1,  Si-Si Liu 1,  Si-Meng Liu 1,  Ming-Jia Yu 3,  Xin-Hong Zhu 4,  Jian-Hua Liang 5
Affiliations

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 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 102488, China. Electronic address: [email protected].
  • 4 Research Center for Brain Health, PazhouLab, Guangzhou, 510330, China. Electronic address: [email protected].
  • 5 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, 102488, China. Electronic address: [email protected].
PMID: 38215588 DOI: 10.1016/j.ejmech.2023.116113
Abstract

Recently, some inhibitors of soluble Epoxide Hydrolase (sEH) showed limited potential in treating sepsis by increasing survival time, but they have unfortunately failed to improve survival rates. In this study, we initially identified a new hit 11D, belonging to a natural skeleton known as stilbene and having an IC50 of 644 nM on inhibiting murine sEH. Natural scaffold-based sEH inhibitors are paid less attention. A combination of structure-activity relationships (SARs)-guided structural optimization and computer-aided skeleton growth led to a highly effective lead compound 70P (IC50: 4.0 nM). The dose-response study indicated that 70P (at doses of 0.5-5 mg/kg, ip.) significantly increased survival rates and survival time by reducing the levels of the inflammatory factors TNF-α and IL-6 in the liver. Interestingly, 70P exhibited much higher accumulation in the liver than in plasma (AUC ratio: 175). In addition, 70P exhibits equal IC50 value (1.5 nM) on inhibiting human sEH as EC5026 (1.7 nM). In conclusion, the natural scaffold-extended sEH inhibitor 70P has the potential to become a new promising lead for addressing the unmet medical need in sepsis treatment, which highlighted the importance of natural skeleton in developing sEH inhibitors.

Keywords

SARs; Sepsis; Stilbene; sEH.

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