Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties
[Display omitted] Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood monon...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-09, Vol.26 (18), p.4455-4461 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | René, Olivier Fauber, Benjamin P. Barnard, Adrian Chapman, Kerry Deng, Yuzhong Eidenschenk, Céline Everett, Christine Gobbi, Alberto Johnson, Adam R. La, Hank Norman, Maxine Salmon, Gary Summerhill, Susan Wong, Harvey |
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Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability. |
| doi_str_mv | 10.1016/j.bmcl.2016.07.081 |
| format | Article |
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Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.07.081</identifier><identifier>PMID: 27524313</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Drug Discovery ; Drug Inverse Agonism ; IL-17 ; Inverse agonist ; Lipids - chemistry ; Naphthalenesulfonates - chemistry ; Nuclear Receptor Subfamily 1, Group F, Member 1 - agonists ; Oxa-sultam ; PBMCs ; RORc ; RORγ</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-09, Vol.26 (18), p.4455-4461</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-b193b764baa807af7c4bd6bf1aa153aeae15b093ccdad195a32aefa99dfcbd0b3</citedby><cites>FETCH-LOGICAL-c455t-b193b764baa807af7c4bd6bf1aa153aeae15b093ccdad195a32aefa99dfcbd0b3</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.2016.07.081$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27524313$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>René, Olivier</creatorcontrib><creatorcontrib>Fauber, Benjamin P.</creatorcontrib><creatorcontrib>Barnard, Adrian</creatorcontrib><creatorcontrib>Chapman, Kerry</creatorcontrib><creatorcontrib>Deng, Yuzhong</creatorcontrib><creatorcontrib>Eidenschenk, Céline</creatorcontrib><creatorcontrib>Everett, Christine</creatorcontrib><creatorcontrib>Gobbi, Alberto</creatorcontrib><creatorcontrib>Johnson, Adam R.</creatorcontrib><creatorcontrib>La, Hank</creatorcontrib><creatorcontrib>Norman, Maxine</creatorcontrib><creatorcontrib>Salmon, Gary</creatorcontrib><creatorcontrib>Summerhill, Susan</creatorcontrib><creatorcontrib>Wong, Harvey</creatorcontrib><title>Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability.</description><subject>Drug Discovery</subject><subject>Drug Inverse Agonism</subject><subject>IL-17</subject><subject>Inverse agonist</subject><subject>Lipids - chemistry</subject><subject>Naphthalenesulfonates - chemistry</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 1 - agonists</subject><subject>Oxa-sultam</subject><subject>PBMCs</subject><subject>RORc</subject><subject>RORγ</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u3CAURlHVqJmmfYEuKpZd1C4YbMZSN1GS_kiJIkWt1B26wHXCyDYu2NPMOi8eRpN2WWUFgnM_xHcIecdZyRlvPm1KM9i-rPK-ZKpka_6CrLhsZCEkq1-SFWsbVqxb-euYvE5pwxiXTMpX5LhSdSUFFyvycO6TDVuMOxo6Gu6hSEs_w5AoJHpzfWOpH_NtQgq3YfRpTjTdhT9-vKUR3WLR0d5PYbrzvbd-3n2kfphiDnQ0YY929tt8SmF0tINtiGB6pKfnVxc0UxPG2WN6Q4466BO-fVpPyM8vFz_OvhWX11-_n51eFlbW9VwY3gqjGmkA1kxBp6w0rjEdB-C1AATktWGtsNaB420NogLsoG1dZ41jRpyQD4fc_PTvBdOsh_x57HsYMSxJ87VQgtdKVM9AueSZVk1GqwNqY0gpYqen6AeIO82Z3nvSG733pPeeNFM6e8pD75_yFzOg-zfyV0wGPh8AzIVsPUadrMcx9-1jblW74P-X_whDzKf2</recordid><startdate>20160915</startdate><enddate>20160915</enddate><creator>René, Olivier</creator><creator>Fauber, Benjamin P.</creator><creator>Barnard, Adrian</creator><creator>Chapman, Kerry</creator><creator>Deng, Yuzhong</creator><creator>Eidenschenk, Céline</creator><creator>Everett, Christine</creator><creator>Gobbi, Alberto</creator><creator>Johnson, Adam R.</creator><creator>La, Hank</creator><creator>Norman, Maxine</creator><creator>Salmon, Gary</creator><creator>Summerhill, Susan</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160915</creationdate><title>Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties</title><author>René, Olivier ; Fauber, Benjamin P. ; Barnard, Adrian ; Chapman, Kerry ; Deng, Yuzhong ; Eidenschenk, Céline ; Everett, Christine ; Gobbi, Alberto ; Johnson, Adam R. ; La, Hank ; Norman, Maxine ; Salmon, Gary ; Summerhill, Susan ; Wong, Harvey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-b193b764baa807af7c4bd6bf1aa153aeae15b093ccdad195a32aefa99dfcbd0b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Drug Discovery</topic><topic>Drug Inverse Agonism</topic><topic>IL-17</topic><topic>Inverse agonist</topic><topic>Lipids - chemistry</topic><topic>Naphthalenesulfonates - chemistry</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 1 - agonists</topic><topic>Oxa-sultam</topic><topic>PBMCs</topic><topic>RORc</topic><topic>RORγ</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>René, Olivier</creatorcontrib><creatorcontrib>Fauber, Benjamin P.</creatorcontrib><creatorcontrib>Barnard, Adrian</creatorcontrib><creatorcontrib>Chapman, Kerry</creatorcontrib><creatorcontrib>Deng, Yuzhong</creatorcontrib><creatorcontrib>Eidenschenk, Céline</creatorcontrib><creatorcontrib>Everett, Christine</creatorcontrib><creatorcontrib>Gobbi, Alberto</creatorcontrib><creatorcontrib>Johnson, Adam R.</creatorcontrib><creatorcontrib>La, Hank</creatorcontrib><creatorcontrib>Norman, Maxine</creatorcontrib><creatorcontrib>Salmon, Gary</creatorcontrib><creatorcontrib>Summerhill, Susan</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>René, Olivier</au><au>Fauber, Benjamin P.</au><au>Barnard, Adrian</au><au>Chapman, Kerry</au><au>Deng, Yuzhong</au><au>Eidenschenk, Céline</au><au>Everett, Christine</au><au>Gobbi, Alberto</au><au>Johnson, Adam R.</au><au>La, Hank</au><au>Norman, Maxine</au><au>Salmon, Gary</au><au>Summerhill, Susan</au><au>Wong, Harvey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-09-15</date><risdate>2016</risdate><volume>26</volume><issue>18</issue><spage>4455</spage><epage>4461</epage><pages>4455-4461</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Modification of the δ-sultam ring of RORc inverse agonist 2 led to the discovery of more polar oxa-sultam 65. The less lipophilic inverse agonist (65) displayed high potency in a biochemical assay, which translated into inhibition of IL-17 production in human peripheral blood mononuclear cells. The successful reduction of lipophilicity of this new analog gave rise to additional improvements in ROR selectivity and aqueous kinetic solubility, as well as reduction in plasma protein binding, while maintaining high cellular permeability.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27524313</pmid><doi>10.1016/j.bmcl.2016.07.081</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2016-09, Vol.26 (18), p.4455-4461 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Drug Discovery Drug Inverse Agonism IL-17 Inverse agonist Lipids - chemistry Naphthalenesulfonates - chemistry Nuclear Receptor Subfamily 1, Group F, Member 1 - agonists Oxa-sultam PBMCs RORc RORγ |
| title | Discovery of oxa-sultams as RORc inverse agonists showing reduced lipophilicity, improved selectivity and favorable ADME properties |
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