Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives
[Display omitted] A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2018-01, Vol.26 (2), p.470-482 |
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| creator | Kono, Mitsunori Oda, Tsuneo Tawada, Michiko Imada, Takashi Banno, Yoshihiro Taya, Naohiro Kawamoto, Tetsuji Tokuhara, Hidekazu Tomata, Yoshihide Ishii, Naoki Ochida, Atsuko Fukase, Yoshiyuki Yukawa, Tomoya Fukumoto, Shoji Watanabe, Hiroyuki Uga, Keiko Shibata, Akira Nakagawa, Hideyuki Shirasaki, Mikio Fujitani, Yasushi Yamasaki, Masashi Shirai, Junya Yamamoto, Satoshi |
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A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. |
| doi_str_mv | 10.1016/j.bmc.2017.12.008 |
| format | Article |
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A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2017.12.008</identifier><identifier>PMID: 29258712</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Autoimmune disease ; IL-17 ; Inverse agonist ; Retinoic acid receptor-related orphan receptor-gamma t (RORγt) ; Tetrahydroisoquinoline ; Th17</subject><ispartof>Bioorganic & medicinal chemistry, 2018-01, Vol.26 (2), p.470-482</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-ea983ab3cb46e8d56d28efa7034a587e5ae8ea80acca00673319880bead482da3</citedby><cites>FETCH-LOGICAL-c423t-ea983ab3cb46e8d56d28efa7034a587e5ae8ea80acca00673319880bead482da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089617319880$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29258712$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kono, Mitsunori</creatorcontrib><creatorcontrib>Oda, Tsuneo</creatorcontrib><creatorcontrib>Tawada, Michiko</creatorcontrib><creatorcontrib>Imada, Takashi</creatorcontrib><creatorcontrib>Banno, Yoshihiro</creatorcontrib><creatorcontrib>Taya, Naohiro</creatorcontrib><creatorcontrib>Kawamoto, Tetsuji</creatorcontrib><creatorcontrib>Tokuhara, Hidekazu</creatorcontrib><creatorcontrib>Tomata, Yoshihide</creatorcontrib><creatorcontrib>Ishii, Naoki</creatorcontrib><creatorcontrib>Ochida, Atsuko</creatorcontrib><creatorcontrib>Fukase, Yoshiyuki</creatorcontrib><creatorcontrib>Yukawa, Tomoya</creatorcontrib><creatorcontrib>Fukumoto, Shoji</creatorcontrib><creatorcontrib>Watanabe, Hiroyuki</creatorcontrib><creatorcontrib>Uga, Keiko</creatorcontrib><creatorcontrib>Shibata, Akira</creatorcontrib><creatorcontrib>Nakagawa, Hideyuki</creatorcontrib><creatorcontrib>Shirasaki, Mikio</creatorcontrib><creatorcontrib>Fujitani, Yasushi</creatorcontrib><creatorcontrib>Yamasaki, Masashi</creatorcontrib><creatorcontrib>Shirai, Junya</creatorcontrib><creatorcontrib>Yamamoto, Satoshi</creatorcontrib><title>Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.</description><subject>Autoimmune disease</subject><subject>IL-17</subject><subject>Inverse agonist</subject><subject>Retinoic acid receptor-related orphan receptor-gamma t (RORγt)</subject><subject>Tetrahydroisoquinoline</subject><subject>Th17</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp9kU1uFDEQRi0EIkPgAGyQlyzSje3u6bFhhRL-pEhBEaytart64pHHDranpT4K5-AenAmPJrBk5Vq8-spVj5CXnLWc8eHNrh33phWMb1ouWsbkI7Li_dA3Xaf4Y7JiapANk2o4I89y3jHGRK_4U3ImlFjLDRcr8vPKZRNnTAuNE40JvF8oTpMzYFw8ZHp7c_v7V6EuVCYjhW0MLpfc0q-QChVv6RVmtw0XNC-h3NU6X1AIlo4u-ritMZ7iDP4AxcVwnBHqNE8LlgR3i03R5fjj4EL0LiC1mNxc0Rnzc_JkAp_xxcN7Tr5__PDt8nNzffPpy-X768b0oisNgpIdjJ0Z-wGlXQ9WSJxgw7oe6o64BpQIkoExwNiw6TqupGQjgu2lsNCdk9en3PtUP4K56H09CXoPAesBNFcbxQe1Vn1F-Qk1KeaccNL3ye0hLZozfTSid7oa0UcjmgtdjdSeVw_xh3GP9l_HXwUVeHcCsC45O0w6G4fBoHUJTdE2uv_E_wErPaDP</recordid><startdate>20180115</startdate><enddate>20180115</enddate><creator>Kono, Mitsunori</creator><creator>Oda, Tsuneo</creator><creator>Tawada, Michiko</creator><creator>Imada, Takashi</creator><creator>Banno, Yoshihiro</creator><creator>Taya, Naohiro</creator><creator>Kawamoto, Tetsuji</creator><creator>Tokuhara, Hidekazu</creator><creator>Tomata, Yoshihide</creator><creator>Ishii, Naoki</creator><creator>Ochida, Atsuko</creator><creator>Fukase, Yoshiyuki</creator><creator>Yukawa, Tomoya</creator><creator>Fukumoto, Shoji</creator><creator>Watanabe, Hiroyuki</creator><creator>Uga, Keiko</creator><creator>Shibata, Akira</creator><creator>Nakagawa, Hideyuki</creator><creator>Shirasaki, Mikio</creator><creator>Fujitani, Yasushi</creator><creator>Yamasaki, Masashi</creator><creator>Shirai, Junya</creator><creator>Yamamoto, Satoshi</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180115</creationdate><title>Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives</title><author>Kono, Mitsunori ; Oda, Tsuneo ; Tawada, Michiko ; Imada, Takashi ; Banno, Yoshihiro ; Taya, Naohiro ; Kawamoto, Tetsuji ; Tokuhara, Hidekazu ; Tomata, Yoshihide ; Ishii, Naoki ; Ochida, Atsuko ; Fukase, Yoshiyuki ; Yukawa, Tomoya ; Fukumoto, Shoji ; Watanabe, Hiroyuki ; Uga, Keiko ; Shibata, Akira ; Nakagawa, Hideyuki ; Shirasaki, Mikio ; Fujitani, Yasushi ; Yamasaki, Masashi ; Shirai, Junya ; Yamamoto, Satoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-ea983ab3cb46e8d56d28efa7034a587e5ae8ea80acca00673319880bead482da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Autoimmune disease</topic><topic>IL-17</topic><topic>Inverse agonist</topic><topic>Retinoic acid receptor-related orphan receptor-gamma t (RORγt)</topic><topic>Tetrahydroisoquinoline</topic><topic>Th17</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kono, Mitsunori</creatorcontrib><creatorcontrib>Oda, Tsuneo</creatorcontrib><creatorcontrib>Tawada, Michiko</creatorcontrib><creatorcontrib>Imada, Takashi</creatorcontrib><creatorcontrib>Banno, Yoshihiro</creatorcontrib><creatorcontrib>Taya, Naohiro</creatorcontrib><creatorcontrib>Kawamoto, Tetsuji</creatorcontrib><creatorcontrib>Tokuhara, Hidekazu</creatorcontrib><creatorcontrib>Tomata, Yoshihide</creatorcontrib><creatorcontrib>Ishii, Naoki</creatorcontrib><creatorcontrib>Ochida, Atsuko</creatorcontrib><creatorcontrib>Fukase, Yoshiyuki</creatorcontrib><creatorcontrib>Yukawa, Tomoya</creatorcontrib><creatorcontrib>Fukumoto, Shoji</creatorcontrib><creatorcontrib>Watanabe, Hiroyuki</creatorcontrib><creatorcontrib>Uga, Keiko</creatorcontrib><creatorcontrib>Shibata, Akira</creatorcontrib><creatorcontrib>Nakagawa, Hideyuki</creatorcontrib><creatorcontrib>Shirasaki, Mikio</creatorcontrib><creatorcontrib>Fujitani, Yasushi</creatorcontrib><creatorcontrib>Yamasaki, Masashi</creatorcontrib><creatorcontrib>Shirai, Junya</creatorcontrib><creatorcontrib>Yamamoto, Satoshi</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kono, Mitsunori</au><au>Oda, Tsuneo</au><au>Tawada, Michiko</au><au>Imada, Takashi</au><au>Banno, Yoshihiro</au><au>Taya, Naohiro</au><au>Kawamoto, Tetsuji</au><au>Tokuhara, Hidekazu</au><au>Tomata, Yoshihide</au><au>Ishii, Naoki</au><au>Ochida, Atsuko</au><au>Fukase, Yoshiyuki</au><au>Yukawa, Tomoya</au><au>Fukumoto, Shoji</au><au>Watanabe, Hiroyuki</au><au>Uga, Keiko</au><au>Shibata, Akira</au><au>Nakagawa, Hideyuki</au><au>Shirasaki, Mikio</au><au>Fujitani, Yasushi</au><au>Yamasaki, Masashi</au><au>Shirai, Junya</au><au>Yamamoto, Satoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2018-01-15</date><risdate>2018</risdate><volume>26</volume><issue>2</issue><spage>470</spage><epage>482</epage><pages>470-482</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29258712</pmid><doi>10.1016/j.bmc.2017.12.008</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Bioorganic & medicinal chemistry, 2018-01, Vol.26 (2), p.470-482 |
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| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Autoimmune disease IL-17 Inverse agonist Retinoic acid receptor-related orphan receptor-gamma t (RORγt) Tetrahydroisoquinoline Th17 |
| title | Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives |
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