Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 146, Issue -, Pages 541-553Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.01.073
Keywords
Chronic pancreatitis; Vitamin D receptor; Extracellular matrix; Pancreatic stellate cells; In vivo; Hypercalcemia
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Funding
- National Natural Science Foundation of China [81773664, 81273468, 81473153]
- National Basic Research Program of China [2015CB755500]
- 111 Project from the Ministry of Education of China
- 111 Project from the State Administration of Foreign Expert Affairs of China [111-2-07]
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Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators. (C) 2018 Elsevier Masson SAS. All rights reserved.
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