Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation

Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38 alpha mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-beta stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-beta/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin1-beta (IL-1 beta) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.

Automated summary

Liver fibrosis is a global health challenge, and developing effective drugs for its treatment is important. Chemically synthesized drugs, especially small molecule pyrazole derivatives as ALK5 inhibitors, have shown promising effects in treating liver fibrosis. In this study, a novel pyrazole derivative, J-1048, was synthesized and its inhibitory effects on ALK5 and p38 alpha MAP kinase were assessed. In vivo and in vitro models were established to explore the mechanisms and therapeutic potential of J-1048. The results demonstrated that J-1048 effectively inhibited TAA-induced liver fibrosis by blocking the TGF-beta/Smad signaling pathway and reducing inflammation. J-1048 has strong potential as a clinical therapeutic candidate for liver fibrosis.