Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis
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 activate...
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| Veröffentlicht in: | European journal of medicinal chemistry 2018-02, Vol.146, p.541-553 |
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| creator | Kang, Zi-Sheng Wang, Cong Han, Xiao-Lin Du, Jun-Jie Li, Yan-Yi Zhang, Can |
| description | 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.
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•A novel series of non-secosteriodal VDR ligands were designed and synthesized.•VDR affinity, transcriptional activity and in vitro anti-fibrosis activity were determined.•Compound 9c were found to significantly inhibit chronic pancreatitis in vivo, without serum calcium increase. |
| doi_str_mv | 10.1016/j.ejmech.2018.01.073 |
| format | Article |
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[Display omitted]
•A novel series of non-secosteriodal VDR ligands were designed and synthesized.•VDR affinity, transcriptional activity and in vitro anti-fibrosis activity were determined.•Compound 9c were found to significantly inhibit chronic pancreatitis in vivo, without serum calcium increase.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2018.01.073</identifier><identifier>PMID: 29407979</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Chronic pancreatitis ; Dose-Response Relationship, Drug ; Drug Design ; Extracellular matrix ; HEK293 Cells ; Humans ; Hypercalcemia ; In vivo ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Pancreatic stellate cells ; Pancreatitis, Chronic - drug therapy ; Receptors, Calcitriol - agonists ; Steroids - chemical synthesis ; Steroids - chemistry ; Steroids - pharmacology ; Structure-Activity Relationship ; Vitamin D receptor</subject><ispartof>European journal of medicinal chemistry, 2018-02, Vol.146, p.541-553</ispartof><rights>2018 Elsevier Masson SAS</rights><rights>Copyright © 2018 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-d3befc556a71bab77ee73efe815cb98a37eff20903c6361f00edc61deb1fe5d83</citedby><cites>FETCH-LOGICAL-c362t-d3befc556a71bab77ee73efe815cb98a37eff20903c6361f00edc61deb1fe5d83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2018.01.073$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29407979$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kang, Zi-Sheng</creatorcontrib><creatorcontrib>Wang, Cong</creatorcontrib><creatorcontrib>Han, Xiao-Lin</creatorcontrib><creatorcontrib>Du, Jun-Jie</creatorcontrib><creatorcontrib>Li, Yan-Yi</creatorcontrib><creatorcontrib>Zhang, Can</creatorcontrib><title>Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>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.
[Display omitted]
•A novel series of non-secosteriodal VDR ligands were designed and synthesized.•VDR affinity, transcriptional activity and in vitro anti-fibrosis activity were determined.•Compound 9c were found to significantly inhibit chronic pancreatitis in vivo, without serum calcium increase.</description><subject>Animals</subject><subject>Chronic pancreatitis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Extracellular matrix</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hypercalcemia</subject><subject>In vivo</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Structure</subject><subject>Pancreatic stellate cells</subject><subject>Pancreatitis, Chronic - drug therapy</subject><subject>Receptors, Calcitriol - agonists</subject><subject>Steroids - chemical synthesis</subject><subject>Steroids - chemistry</subject><subject>Steroids - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Vitamin D receptor</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2OFCEURonROO3oGxjD0oVVXoquotiYmBn_kknc6JpQcOmmUwUtUJ3My_isQ9ujS1cQOPf7AoeQ1wxaBmx4f2jxsKDZtx2wsQXWguBPyIaJYWx412-fkg10HW_6jm-vyIucDwDQDwDPyVUntyCkkBvy-xaz34V3NN-Hsq_7THWwdPJxjjtv9EzxpOdVFx8DjY6GGJqMJuaCyUdb70--6MUHeksTGjyWmOjsd39CUCcfdtTGdZqRZm-Rmr2urKtQbaMloS4LhnKONvsUgzf0qIM5n_vi80vyzOk546vH9Zr8_Pzpx83X5u77l283H-8aw4euNJZP6EzfD1qwSU9CIAqODkfWm0mOmgt0rgMJ3Ax8YA4ArRmYxYk57O3Ir8nbS-4xxV8r5qIWnw3Osw4Y16yYlJJJJoBVdHtBTYo5J3TqmPyi071ioM5m1EFdzKizGQVMVTN17M1jwzotaP8N_VVRgQ8XAOs7Tx6TysZjMGh9_diibPT_b3gAok6mDw</recordid><startdate>20180225</startdate><enddate>20180225</enddate><creator>Kang, Zi-Sheng</creator><creator>Wang, Cong</creator><creator>Han, Xiao-Lin</creator><creator>Du, Jun-Jie</creator><creator>Li, Yan-Yi</creator><creator>Zhang, Can</creator><general>Elsevier Masson SAS</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180225</creationdate><title>Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis</title><author>Kang, Zi-Sheng ; Wang, Cong ; Han, Xiao-Lin ; Du, Jun-Jie ; Li, Yan-Yi ; Zhang, Can</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-d3befc556a71bab77ee73efe815cb98a37eff20903c6361f00edc61deb1fe5d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Chronic pancreatitis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Extracellular matrix</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hypercalcemia</topic><topic>In vivo</topic><topic>Ligands</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Structure</topic><topic>Pancreatic stellate cells</topic><topic>Pancreatitis, Chronic - drug therapy</topic><topic>Receptors, Calcitriol - agonists</topic><topic>Steroids - chemical synthesis</topic><topic>Steroids - chemistry</topic><topic>Steroids - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Vitamin D receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kang, Zi-Sheng</creatorcontrib><creatorcontrib>Wang, Cong</creatorcontrib><creatorcontrib>Han, Xiao-Lin</creatorcontrib><creatorcontrib>Du, Jun-Jie</creatorcontrib><creatorcontrib>Li, Yan-Yi</creatorcontrib><creatorcontrib>Zhang, Can</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kang, Zi-Sheng</au><au>Wang, Cong</au><au>Han, Xiao-Lin</au><au>Du, Jun-Jie</au><au>Li, Yan-Yi</au><au>Zhang, Can</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2018-02-25</date><risdate>2018</risdate><volume>146</volume><spage>541</spage><epage>553</epage><pages>541-553</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><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.
[Display omitted]
•A novel series of non-secosteriodal VDR ligands were designed and synthesized.•VDR affinity, transcriptional activity and in vitro anti-fibrosis activity were determined.•Compound 9c were found to significantly inhibit chronic pancreatitis in vivo, without serum calcium increase.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>29407979</pmid><doi>10.1016/j.ejmech.2018.01.073</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Chronic pancreatitis Dose-Response Relationship, Drug Drug Design Extracellular matrix HEK293 Cells Humans Hypercalcemia In vivo Ligands Male Mice Mice, Inbred C57BL Molecular Structure Pancreatic stellate cells Pancreatitis, Chronic - drug therapy Receptors, Calcitriol - agonists Steroids - chemical synthesis Steroids - chemistry Steroids - pharmacology Structure-Activity Relationship Vitamin D receptor |
| title | Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis |
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