Design, synthesis, biological activity and molecular docking studies of triazolopyridine derivatives as ASK1 inhibitors

Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) is a pivotal mediator in the MAPK pathway, regulating inflammation and fibrosis in Non-alcoholic Steatohepatitis (NASH). A series of novel triazolopyridine derivatives were designed and synthesized as ASK1 inhibitors. Systematic SAR studies identified compound 16a as a potent inhibitor (IC₅₀ = 149.1 nM). Significantly, 16a reduced lipid accumulation in LO2 cells, evidenced by decreased Oil Red O-stained lipid droplets and lowered LDL-C, T-CHO, and TG levels in NASH model cells. Mechanistic studies revealed that 16a suppressed TNF-α-induced activation of the ASK1-p38/JNK signaling pathway in HGC-27 cells and modulated apoptosis-related proteins. These findings highlight 16a as a promising candidate for anti-NASH therapy.