Treatment of rheumatoid arthritis with dissymmetric fluorine and pyridyl-substituted 3,5-bis(aryl)-4-piperidone derivatives by inhibition of NF-KB and MAPK activation

Inhibition of inflammation-related NF-KB and MAPK activation could treat rheumatoid arthritis (RA). Previously, some fluorine-substituted 3,5-bis(aryl)-4-piperidone derivatives (BAPs) exhibited promising anti-inflammatory activity. Herein, interesting structural optimization was carried out and generated thirty-eight dissymmetric fluorine and pyridyl-substituted BAPs (4a-s and 5a-s). They were confirmed by NMR and HRMS. A preliminary structure-activity relationship was summarized and discovered 3,5-CF3 and 3-pyridyl-substituted 4k exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 4k inhibited Lipopolysaccharide-induced nuclear factor kappa-B (NF-KB) and mitogen-activated protein kinase (MAPK) activation by suppressing LPS-induced phosphorylation levels of NF-KB/p65, NF-KB/IKB alpha, c-Jun N-terminal kinase (JNK), extracellular regulated protein kinases (ERK), and NF-KB/p38 in RAW264.7 cells. In vivo, 4k inhibited the development of inflammation and synovial proliferation in rat joint tissues, significantly decreasing paw swelling and arthritis index in adjuvant-induced arthritis rats. More importantly, 4k did not affect body weight and splenic index values. Overall, 4k showed optimistic anti-RA effects, which may be developed as a potential multifunctional agent for the clinical treatment of RA.