2. Academic Validation
  3. Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality

Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality

  • J Med Chem. 2024 Feb 8;67(3):2095-2117. doi: 10.1021/acs.jmedchem.3c02006.
Yuanguang Chen 1,  Jianwen Sun 1,  Hua Tong 2,  Jieru Wang 1,  Ruolin Cao 1,  Huashen Xu 1,  Lu Chen 1,  Christophe Morisseau 3,  Maoying Zhang 1,  Yajie Shi 1,  Chao Han 1,  Junning Zhuang 1,  Yongkui Jing 2,  Zhongbo Liu 4,  Bruce D Hammock 3,  Guoliang Chen 1
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 Liaoning Key Laboratory of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California 95616, United States.
  • 4 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 38236416 DOI: 10.1021/acs.jmedchem.3c02006
Abstract

Epoxyeicosatrienoic acids with anti-inflammatory effects are inactivated by soluble Epoxide Hydrolase (sEH). Both sEH and histone deacetylase 6 (HDAC6) inhibitors are being developed as neuropathic pain relieving agents. Based on the structural similarity, we designed a new group of compounds with inhibition of both HDAC6 and sEH and obtained compound M9. M9 exhibits selective inhibition of HDAC6 over class I HDACs in cells. M9 shows good microsomal stability, moderate plasma protein binding rate, and oral bioavailability. M9 exhibited a strong analgesic effect in vivo, and its analgesic tolerance was better than gabapentin. M9 improved the survival time of mice treated with lipopolysaccharide (LPS) and reversed the levels of inflammatory factors induced by LPS in mouse plasma. M9 represents the first sEH/HDAC6 dual inhibitors with in vivo antineuropathic pain and anti-inflammation.

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