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Discovery and structural optimization of 4-( 4-( benzyloxy)p henyl)-3,4-dihyd ropyrimidin-2(1H )- ones as RORc inverse agonists
Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel R...
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Published in: | 中国药理学报:英文版 2016, Vol.37 (11), p.1516-1524 |
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creator | Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU |
description | Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4- dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17- mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. |
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Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4- dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17- mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><language>eng</language><ispartof>中国药理学报:英文版, 2016, Vol.37 (11), p.1516-1524</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://image.cqvip.com/vip1000/qk/95561A/95561A.jpg</thumbnail><link.rule.ids>314,780,784,4022</link.rule.ids></links><search><creatorcontrib>Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU</creatorcontrib><title>Discovery and structural optimization of 4-( 4-( benzyloxy)p henyl)-3,4-dihyd ropyrimidin-2(1H )- ones as RORc inverse agonists</title><title>中国药理学报:英文版</title><addtitle>Acta Pharmacologica Sinica</addtitle><description>Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4- dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17- mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.</description><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqNjU1OwzAUhC0EEuXnDk-ssWTHTtKu-VF3laruK5O4iVF4Tv1chHsCEFfqnXqFGqkHYDMzi29mLthE1rrkdVHqy5yrWnItpuqa3RC9C6EKJWcT9vvsqPGfNiQw2ALFsGviLpgB_Bjdh9ub6DyC34Dmx8P3Wd8s7tPgv9Lx8DNCbzENOXH1qHnr-tRC8GMKud465EVuyDn8AeDREhiC5WLZgMP8SxZM59FRpDt2tTED2fuz37KH15fV05w3vcdu67Bbj3nUhLSualFNS6Gl-hd0Au8_WnU</recordid><startdate>2016</startdate><enddate>2016</enddate><creator>Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU</creator><scope>2RA</scope><scope>92L</scope><scope>CQIGP</scope><scope>W91</scope><scope>~WA</scope></search><sort><creationdate>2016</creationdate><title>Discovery and structural optimization of 4-( 4-( benzyloxy)p henyl)-3,4-dihyd ropyrimidin-2(1H )- ones as RORc inverse agonists</title><author>Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-chongqing_primary_6706850413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU</creatorcontrib><collection>维普_期刊</collection><collection>中文科技期刊数据库-CALIS站点</collection><collection>维普中文期刊数据库</collection><collection>中文科技期刊数据库-医药卫生</collection><collection>中文科技期刊数据库- 镜像站点</collection><jtitle>中国药理学报:英文版</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and structural optimization of 4-( 4-( benzyloxy)p henyl)-3,4-dihyd ropyrimidin-2(1H )- ones as RORc inverse agonists</atitle><jtitle>中国药理学报:英文版</jtitle><addtitle>Acta Pharmacologica Sinica</addtitle><date>2016</date><risdate>2016</risdate><volume>37</volume><issue>11</issue><spage>1516</spage><epage>1524</epage><pages>1516-1524</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4- dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17- mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.</abstract></addata></record> |
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title | Discovery and structural optimization of 4-( 4-( benzyloxy)p henyl)-3,4-dihyd ropyrimidin-2(1H )- ones as RORc inverse agonists |
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