Title: Discovery of memantyl urea derivatives as potent soluble epoxide hydrolase inhibitors against lipopolysaccharide-induced sepsis.
Authors: Du, Fangyu; Sun, Wenjiao; Morisseau, Christophe; Hammock, Bruce D; Bao, Xuefei; Liu, Qiu; Wang, Chao; Zhang, Tan; Yang, Hao; Zhou, Jun; Xiao, Wei; Liu, Zhongbo; Chen, Guoliang
Published In Eur J Med Chem, (2021 Nov 05)
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.
PubMed ID: 34218083
MeSH Terms: Animals; Binding Sites; Catalytic Domain; Disease Models, Animal; Drug Design; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Enzyme Inhibitors/therapeutic use*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Female; Humans; Lipopolysaccharides/toxicity; Male; Memantine/chemistry*; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Rats; Sepsis/drug therapy*; Sepsis/etiology; Sepsis/mortality; Structure-Activity Relationship; Survival Rate; Urea/analogs & derivatives*; Urea/metabolism; Urea/therapeutic use