Design, synthesis and anti-inflammatory activity on N-(4-(pyridin-4-yloxy)phenyl)-1,4-dihydropyridazine-3-carboxamide derivative z18 for acute lung injury, sepsis and ulcerative colitis models in mice

The pathogenesis of acute lung injury (ALI), sepsis, and ulcerative colitis (UC) is closely interrelated. As inflammatory diseases, they are all characterized by the excessive production of inflammatory cytokines. Therefore, suppression of these cytokines represents a promising therapeutic strategy. Herein, we designed and synthesized a series of N-(4-(pyridin-4-yloxy)phenyl)-1,4-dihydropyridazine-3-carboxamide derivatives based on integrating three structural fragments relating to anti-inflammation. The anti-inflammatory activities of these compounds were evaluated in J774A.1 macrophages, and most compounds effectively inhibited interleukin-6 (IL-6) release in vitro. Compound z18 was identified as the most promising candidate and was further investigated for its dose-dependent effects. Preliminary mechanistic studies indicated that compound z18 suppresses c-Kit kinase activity and subsequently inhibits the NF-κB signaling pathway. z18 exhibited significant anti-inflammatory effects in vivo in LPS-induced ALI, sepsis, and UC mouse models. The preliminary drug-like properties of z18 were also evaluated. z18 demonstrated favorable stability in body fluid stability studies, and its favorable safety profile was further confirmed by subacute toxicity studies. In summary, this study offers novel insights into the design of anti-inflammatory agents and presents z18 as a promising candidate for the treatment of ALI, sepsis, and UC.