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Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2018 Feb 25; Vol. 146, pp. 541-553. Date of Electronic Publication: 2018 Feb 04. - Publication Year :
- 2018
-
Abstract
- 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.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Ligands
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Steroids chemical synthesis
Steroids chemistry
Structure-Activity Relationship
Drug Design
Pancreatitis, Chronic drug therapy
Receptors, Calcitriol agonists
Steroids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 146
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29407979
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.01.073