Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists
[Display omitted] A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activi...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-10, Vol.25 (19), p.4109-4113 |
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| container_end_page | 4113 |
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| container_issue | 19 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 25 |
| creator | Fauber, Benjamin P. Gobbi, Alberto Savy, Pascal Burton, Brenda Deng, Yuzhong Everett, Christine La, Hank Johnson, Adam R. Lockey, Peter Norman, Maxine Wong, Harvey |
| description | [Display omitted]
A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors. |
| doi_str_mv | 10.1016/j.bmcl.2015.08.028 |
| format | Article |
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A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.08.028</identifier><identifier>PMID: 26321361</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Autoimmune ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Inverse Agonism ; Humans ; IL-17 ; Inflammation ; Models, Molecular ; Molecular Structure ; Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists ; Quinolines - chemical synthesis ; Quinolines - chemistry ; Quinolines - pharmacology ; RORc ; RORγ ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-10, Vol.25 (19), p.4109-4113</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-17e989cc79fe425af7d6729b9a9a4537d8c1f051cee68b69aa2fb94979281af3</citedby><cites>FETCH-LOGICAL-c426t-17e989cc79fe425af7d6729b9a9a4537d8c1f051cee68b69aa2fb94979281af3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2015.08.028$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26321361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fauber, Benjamin P.</creatorcontrib><creatorcontrib>Gobbi, Alberto</creatorcontrib><creatorcontrib>Savy, Pascal</creatorcontrib><creatorcontrib>Burton, Brenda</creatorcontrib><creatorcontrib>Deng, Yuzhong</creatorcontrib><creatorcontrib>Everett, Christine</creatorcontrib><creatorcontrib>La, Hank</creatorcontrib><creatorcontrib>Johnson, Adam R.</creatorcontrib><creatorcontrib>Lockey, Peter</creatorcontrib><creatorcontrib>Norman, Maxine</creatorcontrib><creatorcontrib>Wong, Harvey</creatorcontrib><title>Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.</description><subject>Autoimmune</subject><subject>Crystallography, X-Ray</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Inverse Agonism</subject><subject>Humans</subject><subject>IL-17</subject><subject>Inflammation</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists</subject><subject>Quinolines - chemical synthesis</subject><subject>Quinolines - chemistry</subject><subject>Quinolines - pharmacology</subject><subject>RORc</subject><subject>RORγ</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1PwzAURS0EoqXwBxhQRpYE23GcWGJBiI-iikpVBzbLcZ7BVWoXO6nUf0-qFkamt5x7dd9B6JrgjGDC71ZZvdZtRjEpMlxlmFYnaEwYZ2nOcHGKxlhwnFaCfYzQRYwrjAnDjJ2jEeU5JTknY_Q2bcB11litOutd4k3ynsa-Nd7t2rSDLqivXRP8d2-db62DmKiYLOYLnVi3hRAhUZ_e2djFS3RmVBvh6ngnaPn8tHx8TWfzl-njwyzVjPIuJSWISmhdCgOMFsqUDS-pqIUSihV52VSaGFwQDcCrmgulqKkFE6WgFVEmn6DbQ-1mvwpiJ9c2amhb5cD3UZKSkIJxWpQDSg-oDj7GAEZugl2rsJMEy71CuZJ7hXKvUOJKDgqH0M2xv6_X0PxFfp0NwP0BgOHJrYUgo7bgNDQ2gO5k4-1__T-vx4Mi</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Fauber, Benjamin P.</creator><creator>Gobbi, Alberto</creator><creator>Savy, Pascal</creator><creator>Burton, Brenda</creator><creator>Deng, Yuzhong</creator><creator>Everett, Christine</creator><creator>La, Hank</creator><creator>Johnson, Adam R.</creator><creator>Lockey, Peter</creator><creator>Norman, Maxine</creator><creator>Wong, Harvey</creator><general>Elsevier Ltd</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>20151001</creationdate><title>Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists</title><author>Fauber, Benjamin P. ; Gobbi, Alberto ; Savy, Pascal ; Burton, Brenda ; Deng, Yuzhong ; Everett, Christine ; La, Hank ; Johnson, Adam R. ; Lockey, Peter ; Norman, Maxine ; Wong, Harvey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-17e989cc79fe425af7d6729b9a9a4537d8c1f051cee68b69aa2fb94979281af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Autoimmune</topic><topic>Crystallography, X-Ray</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Inverse Agonism</topic><topic>Humans</topic><topic>IL-17</topic><topic>Inflammation</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists</topic><topic>Quinolines - chemical synthesis</topic><topic>Quinolines - chemistry</topic><topic>Quinolines - pharmacology</topic><topic>RORc</topic><topic>RORγ</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fauber, Benjamin P.</creatorcontrib><creatorcontrib>Gobbi, Alberto</creatorcontrib><creatorcontrib>Savy, Pascal</creatorcontrib><creatorcontrib>Burton, Brenda</creatorcontrib><creatorcontrib>Deng, Yuzhong</creatorcontrib><creatorcontrib>Everett, Christine</creatorcontrib><creatorcontrib>La, Hank</creatorcontrib><creatorcontrib>Johnson, Adam R.</creatorcontrib><creatorcontrib>Lockey, Peter</creatorcontrib><creatorcontrib>Norman, Maxine</creatorcontrib><creatorcontrib>Wong, Harvey</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fauber, Benjamin P.</au><au>Gobbi, Alberto</au><au>Savy, Pascal</au><au>Burton, Brenda</au><au>Deng, Yuzhong</au><au>Everett, Christine</au><au>La, Hank</au><au>Johnson, Adam R.</au><au>Lockey, Peter</au><au>Norman, Maxine</au><au>Wong, Harvey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>25</volume><issue>19</issue><spage>4109</spage><epage>4113</epage><pages>4109-4113</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure–activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26321361</pmid><doi>10.1016/j.bmcl.2015.08.028</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-10, Vol.25 (19), p.4109-4113 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Autoimmune Crystallography, X-Ray Dose-Response Relationship, Drug Drug Inverse Agonism Humans IL-17 Inflammation Models, Molecular Molecular Structure Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology RORc RORγ Structure-Activity Relationship |
| title | Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists |
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