{Reference Type}: Journal Article
{Title}: Exploring novel indazole derivatives as ASK1 inhibitors: Design, synthesis, biological evaluation and docking studies.
{Author}: He M;Wang J;Deng W;Han X;Wang X;Pang L;Huang J;Lan P;Wang T;Wang Z;
{Journal}: Bioorg Chem
{Volume}: 147
{Issue}: 0
{Year}: 2024 Jun 22
{Factor}: 5.307
{DOI}: 10.1016/j.bioorg.2024.107391
{Abstract}: Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.