Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents

• Main Authors: Wandong Liu (Author), Caiyun Hou (Author), Jiaming Li (Author), Xiaodong Ma (Author), Yanchun Zhang (Author), Mengqi Hu (Author), Yuanzheng Huang (Author)
• Format: Book
• Published: Taylor & Francis Group, 2020-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1475-6366; 1475-6374; 10.1080/14756366.2019.1693703
• Keywords: polypharmacological agent; anti-inflammation; talmapimod analogues; p38α mapk; coxs; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 187-198 (2020)

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 (IC50=1.95 µM) and COX-2 (IC50=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.