Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor
Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-05, Vol.57 (10), p.4073-4087 |
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| container_title | Journal of medicinal chemistry |
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| creator | Kudo, Takeru Ishizawa, Michiyasu Maekawa, Kazuki Nakabayashi, Makoto Watarai, Yusuke Uchida, Hikaru Tokiwa, Hiroaki Ikura, Teikichi Ito, Nobutoshi Makishima, Makoto Yamada, Sachiko |
| description | Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1–4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10–9–10–8 M with 40–80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure–activity relationships of these compounds on the basis of their X-ray crystal structures. |
| doi_str_mv | 10.1021/jm401989c |
| format | Article |
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However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1–4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10–9–10–8 M with 40–80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure–activity relationships of these compounds on the basis of their X-ray crystal structures.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401989c</identifier><identifier>PMID: 24773565</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adamantane - analogs & derivatives ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Receptors, Calcitriol - agonists ; Receptors, Calcitriol - chemistry ; Structure-Activity Relationship ; Vitamin D - analogs & derivatives</subject><ispartof>Journal of medicinal chemistry, 2014-05, Vol.57 (10), p.4073-4087</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-ee9cbfff7f312b5a8ec0cbce2bea1341286c9d6e2022faed20870b67534229493</citedby><cites>FETCH-LOGICAL-a381t-ee9cbfff7f312b5a8ec0cbce2bea1341286c9d6e2022faed20870b67534229493</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm401989c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401989c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24773565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kudo, Takeru</creatorcontrib><creatorcontrib>Ishizawa, Michiyasu</creatorcontrib><creatorcontrib>Maekawa, Kazuki</creatorcontrib><creatorcontrib>Nakabayashi, Makoto</creatorcontrib><creatorcontrib>Watarai, Yusuke</creatorcontrib><creatorcontrib>Uchida, Hikaru</creatorcontrib><creatorcontrib>Tokiwa, Hiroaki</creatorcontrib><creatorcontrib>Ikura, Teikichi</creatorcontrib><creatorcontrib>Ito, Nobutoshi</creatorcontrib><creatorcontrib>Makishima, Makoto</creatorcontrib><creatorcontrib>Yamada, Sachiko</creatorcontrib><title>Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1–4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10–9–10–8 M with 40–80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure–activity relationships of these compounds on the basis of their X-ray crystal structures.</description><subject>Adamantane - analogs & derivatives</subject><subject>Crystallography, X-Ray</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Receptors, Calcitriol - agonists</subject><subject>Receptors, Calcitriol - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Vitamin D - analogs & derivatives</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMlKBDEURYMo2g4Lf0CyEXRRmqmmZduOIChO2yKVetE0VUmbpBbizxvpVly4CI_AeZd3D0L7lJxQwujpfBCE1lWt1tCE5oxkoiJiHU0IYSxjBeNbaDuEOSGEU8Y30RYTZcnzIp-gz5kbWmNlNM5ip_GTN4se8JmzHZbpTTs5SBulBfxg7CtOVHwD_GKiHIzF5_jRdIBnbzJ97r3rRgUdvpc-Gtnj6auzJsSAtfN_Vh5AwSI6v4s2tOwD7K3mDnq-vHiaXWe3d1c3s-ltJnlFYwZQq1ZrXep0fZvLChRRrQLWgqRcUFYVqu4KYKmtltAxUpWkLcqcC8ZqUfMddLTMXXj3PkKIzWCCgr5PrdwYmqSs4oKUokzo8RJV3oXgQTcLbwbpPxpKmm_Xza_rxB6sYsd2gO6X_JGbgMMlIFVo5m70NrX8J-gLwh6Ffg</recordid><startdate>20140522</startdate><enddate>20140522</enddate><creator>Kudo, Takeru</creator><creator>Ishizawa, Michiyasu</creator><creator>Maekawa, Kazuki</creator><creator>Nakabayashi, Makoto</creator><creator>Watarai, Yusuke</creator><creator>Uchida, Hikaru</creator><creator>Tokiwa, Hiroaki</creator><creator>Ikura, Teikichi</creator><creator>Ito, Nobutoshi</creator><creator>Makishima, Makoto</creator><creator>Yamada, Sachiko</creator><general>American Chemical Society</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>20140522</creationdate><title>Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor</title><author>Kudo, Takeru ; Ishizawa, Michiyasu ; Maekawa, Kazuki ; Nakabayashi, Makoto ; Watarai, Yusuke ; Uchida, Hikaru ; Tokiwa, Hiroaki ; Ikura, Teikichi ; Ito, Nobutoshi ; Makishima, Makoto ; Yamada, Sachiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-ee9cbfff7f312b5a8ec0cbce2bea1341286c9d6e2022faed20870b67534229493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adamantane - analogs & derivatives</topic><topic>Crystallography, X-Ray</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Receptors, Calcitriol - agonists</topic><topic>Receptors, Calcitriol - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Vitamin D - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kudo, Takeru</creatorcontrib><creatorcontrib>Ishizawa, Michiyasu</creatorcontrib><creatorcontrib>Maekawa, Kazuki</creatorcontrib><creatorcontrib>Nakabayashi, Makoto</creatorcontrib><creatorcontrib>Watarai, Yusuke</creatorcontrib><creatorcontrib>Uchida, Hikaru</creatorcontrib><creatorcontrib>Tokiwa, Hiroaki</creatorcontrib><creatorcontrib>Ikura, Teikichi</creatorcontrib><creatorcontrib>Ito, Nobutoshi</creatorcontrib><creatorcontrib>Makishima, Makoto</creatorcontrib><creatorcontrib>Yamada, Sachiko</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kudo, Takeru</au><au>Ishizawa, Michiyasu</au><au>Maekawa, Kazuki</au><au>Nakabayashi, Makoto</au><au>Watarai, Yusuke</au><au>Uchida, Hikaru</au><au>Tokiwa, Hiroaki</au><au>Ikura, Teikichi</au><au>Ito, Nobutoshi</au><au>Makishima, Makoto</au><au>Yamada, Sachiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10–9–10–8 M with 40–80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure–activity relationships of these compounds on the basis of their X-ray crystal structures.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24773565</pmid><doi>10.1021/jm401989c</doi><tpages>15</tpages></addata></record> |
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| subjects | Adamantane - analogs & derivatives Crystallography, X-Ray HEK293 Cells Humans Receptors, Calcitriol - agonists Receptors, Calcitriol - chemistry Structure-Activity Relationship Vitamin D - analogs & derivatives |
| title | Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor |
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