Design, synthesis, and anti-liver fibrosis activity of novel non-steroidal vitamin D receptor agonists based on open-ring steroid scaffold

Vitamin D receptor (VDR) has emerged as a crucial target for the treatment of hepatic fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) components leading to impaired liver function. Activation of VDR has been shown to inhibit the transformation of hepatic stellate cells (HSCs), which play a key role in the development of liver fibrosis, thus reducing ECM production. In this study, a series of 37 non-steroidal VDR agonists with novel scaffold were designed and synthesized utilizing the scaffold hopping strategy. Over one-third of these compounds demonstrated significant VDR affinity and agonistic activity. Among them, compound E15 exhibited the highest VDR agonistic activity, showing promising results in vitro by effectively inhibiting HSC activation. Further in vivo assessments of E15 in a carbon tetrachloride-induced murine model of liver fibrosis demonstrated significant anti-fibrotic activity. Histological analyses revealed a reduction in lesions, inflammatory cell infiltration, and collagen deposition. Concurrently, blood biochemical assays indicated decreased hepatic fibrosis markers and improved serum liver function indices. Notably, E15 achieved these therapeutic effects without inducing hypercalcemia, a common adverse effect associated with VDR agonists such as calcipotriol. These findings underscore the potential of E15 as a potent and safe therapeutic agent for the treatment of liver fibrosis.