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J Med Chem. 2018 Dec 13;61(23):10573-10587. doi: 10.1021/acs.jmedchem.8b01165. Epub 2018 Dec 3.

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

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State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of New Drug Discovery , China Pharmaceutical University , 24 Tong Jia Xiang , Nanjing 210009 , China.
Fujian Provincial Key Laboratory of Hepatic Drug Research , Fuzhou 350001 , China.


Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components and results in impaired liver function. Vitamin D plays a critical role in the development of liver fibrosis as it inhibits transforming growth factor β1 (TGFβ1)-induced excessive deposition of ECM in activated hepatic stellate cells (HSCs). Here, a series of novel nonsecosteroidal vitamin D receptor (VDR) agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized. Among them, seven compounds including 15a exhibited more efficient inhibitory activity in collagen deposition and fibrotic gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis that induced by carbon tetrachloride (CCl4) injections in mice. In addition, compound 15a, unlike the positive control calcipotriol and 1,25(OH)2D3, did not cause hypercalcemia that is toxic to nerve, heart, and many other organs. These findings provide novel insights into drug discoveries for hepatic fibrosis using nonsecosteroidal VDR modulators.

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