2. Academic Validation
  3. Design and synthesis of novel sEH inhibitors for the treatment of acute lung injury

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

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: 546265581@qq.com.
  • 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: caoruolin2021@163.com.
  • 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: chenguoliang@syphu.edu.cn.
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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