Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents.

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  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
    • Subject Terms:
      Drug Discovery*; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cyclooxygenase 2/*metabolism ; NF-kappa B/*antagonists & inhibitors ; Nitric Oxide Synthase Type II/*antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/*antagonists & inhibitors; Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Lipopolysaccharides/antagonists & inhibitors ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Molecular Structure ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; RAW 264.7 Cells ; Signal Transduction/drug effects ; Structure-Activity Relationship ; p38 Mitogen-Activated Protein Kinases/metabolism
    • Abstract:
      Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n , the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC 50 =1.95 µM) and COX-2 (IC 50 =0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n , a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.
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    • Contributed Indexing:
      Keywords: COXs; Polypharmacological agent; anti-inflammation; p38α MAPK; talmapimod analogues
    • Accession Number:
      0 (Anti-Inflammatory Agents, Non-Steroidal)
      0 (Lipopolysaccharides)
      0 (NF-kappa B)
      EC 1.14.13.39 (Nitric Oxide Synthase Type II)
      EC 1.14.99.1 (Cyclooxygenase 2)
      EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
    • Publication Date:
      Date Created: 20191123 Date Completed: 20200113 Latest Revision: 20210507
    • Publication Date:
      20240104
    • Accession Number:
      PMC6882468
    • Accession Number:
      10.1080/14756366.2019.1693703
    • Accession Number:
      31752552