A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy
In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2013-04, Vol.21 (7), p.1823-1833 |
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| creator | Kashiwagi, Hirotaka Ono, Yoshiyuki Ohta, Masateru Itoh, Susumu Ichikawa, Fumihiko Harada, Suguru Takeda, Satoshi Sekiguchi, Nobuo Ishigai, Masaki Takahashi, Tadakatsu |
| description | In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human. |
| doi_str_mv | 10.1016/j.bmc.2013.01.042 |
| format | Article |
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These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2013.01.042</identifier><identifier>PMID: 23453218</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acetic acid ; agonists ; animal models ; Animals ; Benzhydryl Compounds - chemistry ; Benzhydryl Compounds - pharmacokinetics ; Benzhydryl Compounds - pharmacology ; Benzhydryl Compounds - therapeutic use ; bone density ; Bone Density - drug effects ; Cell Line ; CH5036249 ; chemistry ; cholecalciferol ; Cholecalciferol - analogs & derivatives ; Cholecalciferol - pharmacokinetics ; Cholecalciferol - pharmacology ; Cholecalciferol - therapeutic use ; Crystallography, X-Ray ; drugs ; Humans ; hypercalcemia ; Male ; Models, Molecular ; Molecular Docking Simulation ; Nonsecosteroid ; Osteocalcin - metabolism ; Osteoporosis ; Osteoporosis - drug therapy ; Osteoporosis - metabolism ; Pyridines - chemistry ; Pyridines - pharmacokinetics ; Pyridines - pharmacology ; Pyridines - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Calcitriol - agonists ; Receptors, Calcitriol - metabolism ; screening ; therapeutics ; VDR agonist ; Vitamin D3 ; X-radiation</subject><ispartof>Bioorganic & medicinal chemistry, 2013-04, Vol.21 (7), p.1823-1833</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-cc847ad32c588610bea0b4b2720054b0b62170d5359fd44ab042e90d710d291c3</citedby><cites>FETCH-LOGICAL-c509t-cc847ad32c588610bea0b4b2720054b0b62170d5359fd44ab042e90d710d291c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089613000813$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23453218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kashiwagi, Hirotaka</creatorcontrib><creatorcontrib>Ono, Yoshiyuki</creatorcontrib><creatorcontrib>Ohta, Masateru</creatorcontrib><creatorcontrib>Itoh, Susumu</creatorcontrib><creatorcontrib>Ichikawa, Fumihiko</creatorcontrib><creatorcontrib>Harada, Suguru</creatorcontrib><creatorcontrib>Takeda, Satoshi</creatorcontrib><creatorcontrib>Sekiguchi, Nobuo</creatorcontrib><creatorcontrib>Ishigai, Masaki</creatorcontrib><creatorcontrib>Takahashi, Tadakatsu</creatorcontrib><title>A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.</description><subject>Acetic acid</subject><subject>agonists</subject><subject>animal models</subject><subject>Animals</subject><subject>Benzhydryl Compounds - chemistry</subject><subject>Benzhydryl Compounds - pharmacokinetics</subject><subject>Benzhydryl Compounds - pharmacology</subject><subject>Benzhydryl Compounds - therapeutic use</subject><subject>bone density</subject><subject>Bone Density - drug effects</subject><subject>Cell Line</subject><subject>CH5036249</subject><subject>chemistry</subject><subject>cholecalciferol</subject><subject>Cholecalciferol - analogs & derivatives</subject><subject>Cholecalciferol - pharmacokinetics</subject><subject>Cholecalciferol - pharmacology</subject><subject>Cholecalciferol - therapeutic use</subject><subject>Crystallography, X-Ray</subject><subject>drugs</subject><subject>Humans</subject><subject>hypercalcemia</subject><subject>Male</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Nonsecosteroid</subject><subject>Osteocalcin - metabolism</subject><subject>Osteoporosis</subject><subject>Osteoporosis - drug therapy</subject><subject>Osteoporosis - metabolism</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Calcitriol - agonists</subject><subject>Receptors, Calcitriol - metabolism</subject><subject>screening</subject><subject>therapeutics</subject><subject>VDR agonist</subject><subject>Vitamin D3</subject><subject>X-radiation</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi1ERZfCD-ACPnJJmLGdxBanquVLqlRV0LPlOJPi1SYOdrZS_3292sIROFmWnnntdx7G3iDUCNh-2Nb95GsBKGvAGpR4xjaoWlVJafA524BpdQXatKfsZc5bABDK4At2KqRqpEC9YTfnPFMKlHkc-RznTD7mlVIMg9vx-7C6Kcz8kifytKwxcXcX55DXzMdyOaBxiSnmkPn6k5JbHl6xk9HtMr1-Os_Y7edPPy6-VlfXX75dnF9VvgGzVt5r1blBCt9o3SL05KBXvegEQKN66FuBHQyNbMw4KOX6Uo8MDB3CIAx6ecbeH3OXFH_tKa92CtnTbudmivtssQHojAQh_o1KITW2Lej_QLHTjTBKFRSPqC_9c6LRLilMLj1YBHvwY7e2-LEHPxbQlgJl5u1T_L6faPgz8VtIAd4dgdFF6-5SyPb2e0koZRBBd4dnPx4JKsu9D5Rs9oFmT0MoklY7xPCXDzwCIvyoDA</recordid><startdate>20130401</startdate><enddate>20130401</enddate><creator>Kashiwagi, Hirotaka</creator><creator>Ono, Yoshiyuki</creator><creator>Ohta, Masateru</creator><creator>Itoh, Susumu</creator><creator>Ichikawa, Fumihiko</creator><creator>Harada, Suguru</creator><creator>Takeda, Satoshi</creator><creator>Sekiguchi, Nobuo</creator><creator>Ishigai, Masaki</creator><creator>Takahashi, Tadakatsu</creator><general>Elsevier Ltd</general><scope>FBQ</scope><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><scope>7QO</scope><scope>7QP</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20130401</creationdate><title>A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy</title><author>Kashiwagi, Hirotaka ; Ono, Yoshiyuki ; Ohta, Masateru ; Itoh, Susumu ; Ichikawa, Fumihiko ; Harada, Suguru ; Takeda, Satoshi ; Sekiguchi, Nobuo ; Ishigai, Masaki ; Takahashi, Tadakatsu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-cc847ad32c588610bea0b4b2720054b0b62170d5359fd44ab042e90d710d291c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acetic acid</topic><topic>agonists</topic><topic>animal models</topic><topic>Animals</topic><topic>Benzhydryl Compounds - chemistry</topic><topic>Benzhydryl Compounds - pharmacokinetics</topic><topic>Benzhydryl Compounds - pharmacology</topic><topic>Benzhydryl Compounds - therapeutic use</topic><topic>bone density</topic><topic>Bone Density - drug effects</topic><topic>Cell Line</topic><topic>CH5036249</topic><topic>chemistry</topic><topic>cholecalciferol</topic><topic>Cholecalciferol - analogs & derivatives</topic><topic>Cholecalciferol - pharmacokinetics</topic><topic>Cholecalciferol - pharmacology</topic><topic>Cholecalciferol - therapeutic use</topic><topic>Crystallography, X-Ray</topic><topic>drugs</topic><topic>Humans</topic><topic>hypercalcemia</topic><topic>Male</topic><topic>Models, Molecular</topic><topic>Molecular Docking Simulation</topic><topic>Nonsecosteroid</topic><topic>Osteocalcin - metabolism</topic><topic>Osteoporosis</topic><topic>Osteoporosis - drug therapy</topic><topic>Osteoporosis - metabolism</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - pharmacology</topic><topic>Pyridines - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Calcitriol - agonists</topic><topic>Receptors, Calcitriol - metabolism</topic><topic>screening</topic><topic>therapeutics</topic><topic>VDR agonist</topic><topic>Vitamin D3</topic><topic>X-radiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kashiwagi, Hirotaka</creatorcontrib><creatorcontrib>Ono, Yoshiyuki</creatorcontrib><creatorcontrib>Ohta, Masateru</creatorcontrib><creatorcontrib>Itoh, Susumu</creatorcontrib><creatorcontrib>Ichikawa, Fumihiko</creatorcontrib><creatorcontrib>Harada, Suguru</creatorcontrib><creatorcontrib>Takeda, Satoshi</creatorcontrib><creatorcontrib>Sekiguchi, Nobuo</creatorcontrib><creatorcontrib>Ishigai, Masaki</creatorcontrib><creatorcontrib>Takahashi, Tadakatsu</creatorcontrib><collection>AGRIS</collection><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><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kashiwagi, Hirotaka</au><au>Ono, Yoshiyuki</au><au>Ohta, Masateru</au><au>Itoh, Susumu</au><au>Ichikawa, Fumihiko</au><au>Harada, Suguru</au><au>Takeda, Satoshi</au><au>Sekiguchi, Nobuo</au><au>Ishigai, Masaki</au><au>Takahashi, Tadakatsu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2013-04-01</date><risdate>2013</risdate><volume>21</volume><issue>7</issue><spage>1823</spage><epage>1833</epage><pages>1823-1833</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>In an extension of our study on gamma hydroxy carboxylic acid analogs, we explored a series of nonsecosteroidal vitamin D receptor (VDR) agonists in which 1,3-diol of 1,25(OH)2D3 had been replaced by aryl acetic acid. These analogs showed very potent activity in vitro compared with 1,25(OH)2D3. An X-ray analysis of 8d showed that the inserted phenyl ring well mimicked the folded methylene linker of the gamma hydroxy carboxylic acid moiety but the carboxylic acid of 8d interacted with VDR in a different manner from gamma hydroxy carboxylic acids. Through our in vivo screening in an osteoporosis rat model using immature rats, we identified a potent active vitamin D3 analog, compound 7e. In mature rats of the same model, compound 7e also showed good PK profiling and excellent ability to prevent bone mineral density loss without severe hypercalcemia. Our nonsecosteroidal VDR agonist 7e (CH5036249) could be a possible new drug candidate for treating osteoporosis in human.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23453218</pmid><doi>10.1016/j.bmc.2013.01.042</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry, 2013-04, Vol.21 (7), p.1823-1833 |
| issn | 0968-0896 1464-3391 |
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| subjects | Acetic acid agonists animal models Animals Benzhydryl Compounds - chemistry Benzhydryl Compounds - pharmacokinetics Benzhydryl Compounds - pharmacology Benzhydryl Compounds - therapeutic use bone density Bone Density - drug effects Cell Line CH5036249 chemistry cholecalciferol Cholecalciferol - analogs & derivatives Cholecalciferol - pharmacokinetics Cholecalciferol - pharmacology Cholecalciferol - therapeutic use Crystallography, X-Ray drugs Humans hypercalcemia Male Models, Molecular Molecular Docking Simulation Nonsecosteroid Osteocalcin - metabolism Osteoporosis Osteoporosis - drug therapy Osteoporosis - metabolism Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - pharmacology Pyridines - therapeutic use Rats Rats, Sprague-Dawley Receptors, Calcitriol - agonists Receptors, Calcitriol - metabolism screening therapeutics VDR agonist Vitamin D3 X-radiation |
| title | A series of nonsecosteroidal vitamin D receptor agonists for osteoporosis therapy |
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