Compound(Sailong)

Chronic liver diseases activate hepatic stellate cells (HSCs), driving excessive deposition of extracellular matrix (ECM) and leading to liver fibrosis. Despite being a crucial precursor to cirrhosis, effective targeted antifibrotic therapies are lacking. Activation of the vitamin D receptor (VDR) has been shown to effectively alleviate liver fibrosis, yet prolonged use of currently available steroidal VDR agonists can lead to hypercalcemia. To address this issue, we performed structural optimization targeting the CD-ring and conjugated triene moiety, while preserving the A-ring and side chains, yielding 52 novel nonsteroidal VDR modulators. Among them, compounds A17, B15, and B20 demonstrated favorable VDR binding affinity and potent antifibrotic activity in vitro. Notably, compound B15 significantly reduced fibrosis without inducing hypercalcemia in a murine model of carbon tetrachloride (CCl₄)-induced liver fibrosis. These findings highlight the potential of these nonsteroidal VDR modulators and warrant further investigation as promising therapeutics for liver fibrosis.

Twenty‐eight isoaurone derivatives with 1,2,4‐triazole moieties were synthesized using a fragment‐based design strategy, and their anti‐inflammatory activity was investigated. The anti‐inflammatory effect of the most active derivative, 14e (41.82 %), was dose‐dependent and higher than the values for celecoxib (31.82 %). Compound 14e was almost non‐toxic and inhibited different concentrations of nitric oxide (NO). The western blotting results demonstrated that cyclooxygenase‐2 (COX‐2) expression was elevated when the macrophages were exclusively treated with LPS. However, compound 14e effectively suppressed the LPS‐induced COX‐2 upregulation. Subsequent investigation revealed that 14e is a promising compound capable of inhibiting the downstream signaling of COX‐2. With the above interesting biological profile, molecular 14e could be a promising lead to develop novel anti‐inflammatory agents.