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New advances of novel non-steroidal vitamin D derivatives against hepatic fibrosis
Submission:张灿课题组  Date:2018-11-05   Page View:10

Hepatic fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and impaired liver function. Transforming growth factor β1 (TGFβ1) plays a key role in the induction of hepatic stellate cell (HSC) activation, which is characterized by up-regulation of α-smooth muscle actin (α-SMA); activated HSC produces excess collagen, thickening extracellular matrix. Inhibition of the activation of the TGFβ1 pathway plays an important role in reversing liver fibrosis. Over-expressed vitamin D receptor (VDR) was found on the surface of activated HSC. Studies have shown that vitamin D analogue 1,25(OH)2D3 can inhibit the progression of liver fibrosis. The possible mechanism might be  that activating VDR inhibits the binding of SMAD3 to its action sites in the downstream pathway, thereby reducing the transcriptional expression of collagenase and α-SMA; while the proteins of SMAD family play a role in the transmission of TGF-β signaling from cell surface receptors to the nucleus. Based on this, VDR agonists may antagonize the extensive transcription and expression of profibrotic genes that are dependent on the TGFβ/SMAD signaling pathway, which plays a important role for anti-fibrosis.

Compound No.15 and the 

In recent years, our research group has achieved fruitful results in the field of VDR agonists. Several new VDR agonist molecular entities against tumor have been published in the early stage. In this study, we designed and synthesized a series of novel VDR agonists with phenylpyrrolylpentane skeleton against liver fibrosis. Seven compounds showed the ability to inhibite collagen deposition and fibrosis-related gene expression. The activity of the compound No. 15a was optimal. Histopathological section results showed that 15a could effectively prevent the development of liver fibrosis induced by carbon tetrachloride in mice. In addition, compound 15a caused lower hypercalcemia toxicity than the positive drug calcipotriol and 1,25(OH)2D3, which was  potential for intensive research and development.

This work provides a new perspective for the development of anti-fibrosis drugs and is expected to promote the development of new drugs in this field. The results were published in the Journal of Medicinal Chemistry. Dr. Wang Cong and Dr. Wang Bin are the co-first authors of this article, and Professor Zhang Can is the corresponding author.

Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton.pdf