Design, Synthesis, and Evaluation of Antifibrotic Activity of Nonsteroidal VDR Agonists Featuring 1,6-Naphthol as a CD-Ring Surrogate

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.