Synthesis and biological evaluation of new series of benzamide derivatives containing urea moiety as sEH inhibitors

  • Bioorg Med Chem Lett. 2022 Aug 15;70:128805. doi: 10.1016/j.bmcl.2022.128805.
Ye Tian  1 ,  Shuo Li  2 ,  Peiyao Yang  1 ,  Xiaolu Su  2 ,  Jialu Liu  1 ,  Xuening Lv  2 ,  Kuan Dong  1 ,  Ting Yang  2 ,  Meibo Duan  1 ,  Guangda Hu  2 ,  Hao Yue  1 ,  Yanping Sun  2 ,  Yongjun Sun  2 ,  Huimin Zhang  2 ,  Zhidian Du  2 ,  Zhenyu Miao  3 ,  Minghui Tong  3 ,  Yunlei Hou  1 ,  Zibin Gao  4 ,  Yanfang Zhao  5
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2. State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, PR China.
  • 3. 3D BioOptima Co,. Ltd., Suzhou 215104, PR China.
  • 4. State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, PR China. Electronic address: [email protected].
  • 5. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 35598794 DOI: 10.1016/j.bmcl.2022.128805
Abstract

The pharmacological inhibition of soluble Epoxide Hydrolase (sEH) was shown to reduce inflammation and pain. Herein, we described a series of newly synthesized sEH inhibitors with the trident-shaped skeleton. Intensive structural modifications led to the identification of compound B15 as a potent sEH inhibitor with an IC50 value of 0.03 ± 0.01 nM. Furthermore, compound B15 showed satisfactory metabolic stability in human liver microsomes with a half-time of 197 min. In carrageenan-induced inflammatory pain rat model, compound B15 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib, which demonstrated the proof of potential as anti-inflammatory agents for pain relief.

Keywords
Benzamide derivatives; In vivo anti-inflammation; SEH inhibitor.
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