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

Yi Gao1, Yue Wu1, Chun Guan1

  • 1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, P. R. China.

Journal of Medicinal Chemistry
|September 19, 2025
PubMed

Insights

New nonsteroidal vitamin D receptor (VDR) modulators show promise for treating liver fibrosis. Compound B15 effectively reduced liver fibrosis in mice without causing hypercalcemia, offering a potential new therapeutic avenue.

Area of Science:

  • Hepatology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Chronic liver diseases activate hepatic stellate cells (HSCs), leading to extracellular matrix (ECM) deposition and liver fibrosis, a precursor to cirrhosis.
  • Current antifibrotic therapies are limited, and while vitamin D receptor (VDR) activation shows efficacy, steroidal VDR agonists cause hypercalcemia.

Purpose of the Study:

  • To develop novel nonsteroidal VDR modulators to treat liver fibrosis without hypercalcemia.
  • To identify specific compounds with potent antifibrotic activity and favorable VDR binding.

Main Methods:

  • Structural optimization of VDR modulators targeting the CD-ring and conjugated triene moiety.
  • Synthesis of 52 novel nonsteroidal VDR modulators.
  • In vitro assessment of VDR binding affinity and antifibrotic activity.
  • In vivo evaluation of compound B15 in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model.

Main Results:

  • Compounds A17, B15, and B20 exhibited significant VDR binding affinity and potent in vitro antifibrotic activity.
  • Compound B15 demonstrated substantial reduction in liver fibrosis in vivo.
  • Compound B15 did not induce hypercalcemia in the murine model.

Conclusions:

  • Novel nonsteroidal VDR modulators, particularly compound B15, show significant potential as therapeutics for liver fibrosis.
  • These compounds offer a promising alternative to steroidal VDR agonists by avoiding hypercalcemia.
  • Further investigation is warranted to explore their clinical application for liver fibrosis treatment.

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