Design and synthesis of novel sEH inhibitors for the treatment of acute lung injury

  • Eur J Med Chem. 2026 May 5:309:118773. doi: 10.1016/j.ejmech.2026.118773.
Huashen Xu  1 ,  Ruiyi Ma  1 ,  Christophe Morisseau  2 ,  Xinyue Dong  3 ,  Junning Zhuang  1 ,  Zhe Wang  1 ,  Fuqin Liu  1 ,  Dong Xu  1 ,  Lu Chen  1 ,  Maoying Zhang  1 ,  Zhihui Zhu  3 ,  Xinran Liu  1 ,  Huiwen Jiang  1 ,  Zhongbo Liu  4 ,  Bruce D Hammock  2 ,  Ruolin Cao  5 ,  Guoliang Chen  6
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, 95616, USA.
  • 3. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 4. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 5. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 6. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 41844112 DOI: 10.1016/j.ejmech.2026.118773
Abstract

Inflammatory response and oxidative stress play important roles in the development of Acute Lung Injury (ALI). In the current study, we discovered a series of soluble Epoxide Hydrolase (sEH) inhibitors containing bis-urea scaffold that potently inhibited the generations of various inflammatory factors mediated by NF-κB activation and ROS. Especially, lead compound 20k showed potent inhibitory activities against sEH (20k; HsEH IC50 = 0.8 nM, MsEH IC50 = 0.7 nM). Compound 20k exhibited excellently intraperitoneal bioavailability (F = 125.90%). In vivo, 20k showed a strong anti-inflammatory activity in ALI models and decreased the release of IL-1β, IL-6 and TNF-α. More importantly, 20k reduced expression of MPO and prevented polarization of macrophage M1. In addition, 20k was well-tolerated in a subacute safety evaluation at a high dose of 2 g/kg/day. Overall, this study demonstrated the potential of 20k as a promising lead compound for ALI therapy, which merited further investigation.

Keywords
Acute lung injury; Anti-inflammatory; Inhibitors; Soluble epoxide hydrolase; Synthesis.
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