II-8

Hepatic fibrosis, a pathological consequence of chronic liver injury, is characterized by excessive deposition of extracellular matrix (ECM). Activation of hepatic stellate cells (HSCs) is critical to the pathogenesis. Vitamin D receptor (VDR) agonists have been demonstrated to inhibit transforming growth factor-beta 1 (TGF-β1) induced HSC activation, thereby reducing ECM deposition and attenuating the progression of liver fibrosis. Despite their broad therapeutic potential, the clinical translation of VDR agonists has been hampered by the risk of inducing hypercalcemia. To address this limitation, we designed a series of novel non-steroidal VDR agonists based on a phenylindole scaffold and evaluated their anti-fibrotic properties. Among them, compounds I-7, II-4, II-6, and II-8, exhibited significant inhibition of HSC activation in vitro. Owing to its robust activity, compound II-8 was selected for further investigation in a bile duct ligation (BDL)-induced liver fibrosis model. Histological analysis confirmed that treatment with II-8 significantly inhibited the fibrosis progression. Crucially, the hypercalcemia typically associated with VDR agonist therapy was not observed. Hypercalcemia is a major drawback of currently marketed steroidal VDR agonists, which significantly limits their broad clinical application. The compounds we have designed can effectively avoid this hypercalcemia side effect. These findings underscore the potential of II-8 as a potent therapeutic agent for the treatment of liver fibrosis.