2. Academic Validation
  3. Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis

Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis

  • Eur J Med Chem. 2021 Nov 5;223:113678. doi: 10.1016/j.ejmech.2021.113678.
Fangyu Du 1,  Wenjiao Sun 1,  Christophe Morisseau 2,  Bruce D Hammock 2,  Xuefei Bao 3,  Qiu Liu 4,  Chao Wang 4,  Tan Zhang 4,  Hao Yang 4,  Jun Zhou 4,  Wei Xiao 5,  Zhongbo Liu 6,  Guoliang Chen 7
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China.
  • 2 Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China; Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangning Industrial City, Economic and Technological Development Zone, Lianyungang, Jiangsu, 222001, China.
  • 4 Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangning Industrial City, Economic and Technological Development Zone, Lianyungang, Jiangsu, 222001, China.
  • 5 Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangning Industrial City, Economic and Technological Development Zone, Lianyungang, Jiangsu, 222001, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
  • 7 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China. Electronic address: [email protected].
PMID: 34218083 DOI: 10.1016/j.ejmech.2021.113678
Abstract

Sepsis, a systemic inflammatory response, caused by pathogenic factors including Microorganisms, has high mortality and limited therapeutic approaches. Herein, a new soluble Epoxide Hydrolase (sEH) inhibitor series comprising a phenyl ring connected to a memantyl moiety via a urea or amide linkage has been designed. A preferential urea pharmacophore that improved the binding properties of the compounds was identified for those series via biochemical assay in vitro and in vivo studies. Molecular docking displayed that 3,5-dimethyl on the adamantyl group in B401 could make van der Waals interactions with residues at a hydrophobic pocket of sEH active site, which might indirectly explain the subnanomolar level activities of memantyl urea derivatives in vitro better than AR-9281. Among them, compound B401 significantly improved the inhibition potency with human and murine sEH IC50 values as 0.4 nM and 0.5 nM, respectively. Although the median survival time of C57BL/6 mice in LPS-induced sepsis model was slightly increased, the survival rate did not reach significant efficacy. Based on safety profile, metabolic stability, pharmacokinetic and in vivo efficacy, B401 demonstrated the proof of potential for this class of memantyl urea-based sEH inhibitors as therapeutic agents in sepsis.

Keywords

Cytokine storm; Memantine derivatives; Sepsis; Soluble epoxide hydrolase.

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