Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold
[Display omitted] Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood a...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2021-02, Vol.33, p.127738-127738, Article 127738 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 33 |
| creator | Kinzel, Olaf Steeneck, Christoph Anderhub, Simon Hornberger, Martin Pinto, Sheena Morschhaeuser, Barbara Albers, Michael Sonnek, Christina Wang, Yansong Mallinger, Aurélie Czekańska, Marta Hoffmann, Thomas |
| description | [Display omitted]
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1). |
| doi_str_mv | 10.1016/j.bmcl.2020.127738 |
| format | Article |
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Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2020.127738</identifier><identifier>PMID: 33316404</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Cancer immunotherapy ; Heme-displacer ; IDO1 ; Indoleamine-2,3-dioxygenase-1 ; Spirofused ; Tryptophan-kynurenine-AhR-pathway</subject><ispartof>Bioorganic & medicinal chemistry letters, 2021-02, Vol.33, p.127738-127738, Article 127738</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-4514722c7a543df1d2abad49c38916c6eeff6bfee326b1fb84195c37cc5284a93</citedby><cites>FETCH-LOGICAL-c356t-4514722c7a543df1d2abad49c38916c6eeff6bfee326b1fb84195c37cc5284a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X20308490$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33316404$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kinzel, Olaf</creatorcontrib><creatorcontrib>Steeneck, Christoph</creatorcontrib><creatorcontrib>Anderhub, Simon</creatorcontrib><creatorcontrib>Hornberger, Martin</creatorcontrib><creatorcontrib>Pinto, Sheena</creatorcontrib><creatorcontrib>Morschhaeuser, Barbara</creatorcontrib><creatorcontrib>Albers, Michael</creatorcontrib><creatorcontrib>Sonnek, Christina</creatorcontrib><creatorcontrib>Wang, Yansong</creatorcontrib><creatorcontrib>Mallinger, Aurélie</creatorcontrib><creatorcontrib>Czekańska, Marta</creatorcontrib><creatorcontrib>Hoffmann, Thomas</creatorcontrib><title>Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).</description><subject>Cancer immunotherapy</subject><subject>Heme-displacer</subject><subject>IDO1</subject><subject>Indoleamine-2,3-dioxygenase-1</subject><subject>Spirofused</subject><subject>Tryptophan-kynurenine-AhR-pathway</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kEtr3DAUhUVJaSZp_0AXRctsPNXLsg3ZhEwfgUA2LXQnpKurjAbbciRPYP59PEyaZVb3wTkHzkfIV87WnHH9fbd2A_RrwcTyEE0j2w9kxZVWlVSsPiMr1mlWtZ36d04uStkxxhVT6hM5l1Jyvewr4jaxQHrGfKAp0G183PYHOqUZx5luccDKxzL1FuL4SO82D5zGcRtdnFMu1NmCnqaRWlqmmFPYH28X4QB9BFrAhpB6_5l8DLYv-OV1XpK_P3_8uf1d3T_8uru9ua9A1nquVM1VIwQ0tlbSB-6FddarDmTbcQ0aMQTtAqIU2vHgWsW7GmQDUItW2U5ekqtT7pTT0x7LbIalG_a9HTHtixGqYaIVXLJFKk5SyKmUjMFMOQ42Hwxn5sjW7MyRrTmyNSe2i-nba_7eDejfLP9hLoLrkwCXls8RsykQcQT0MSPMxqf4Xv4LwrCLOA</recordid><startdate>20210201</startdate><enddate>20210201</enddate><creator>Kinzel, Olaf</creator><creator>Steeneck, Christoph</creator><creator>Anderhub, Simon</creator><creator>Hornberger, Martin</creator><creator>Pinto, Sheena</creator><creator>Morschhaeuser, Barbara</creator><creator>Albers, Michael</creator><creator>Sonnek, Christina</creator><creator>Wang, Yansong</creator><creator>Mallinger, Aurélie</creator><creator>Czekańska, Marta</creator><creator>Hoffmann, Thomas</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20210201</creationdate><title>Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold</title><author>Kinzel, Olaf ; Steeneck, Christoph ; Anderhub, Simon ; Hornberger, Martin ; Pinto, Sheena ; Morschhaeuser, Barbara ; Albers, Michael ; Sonnek, Christina ; Wang, Yansong ; Mallinger, Aurélie ; Czekańska, Marta ; Hoffmann, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-4514722c7a543df1d2abad49c38916c6eeff6bfee326b1fb84195c37cc5284a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cancer immunotherapy</topic><topic>Heme-displacer</topic><topic>IDO1</topic><topic>Indoleamine-2,3-dioxygenase-1</topic><topic>Spirofused</topic><topic>Tryptophan-kynurenine-AhR-pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kinzel, Olaf</creatorcontrib><creatorcontrib>Steeneck, Christoph</creatorcontrib><creatorcontrib>Anderhub, Simon</creatorcontrib><creatorcontrib>Hornberger, Martin</creatorcontrib><creatorcontrib>Pinto, Sheena</creatorcontrib><creatorcontrib>Morschhaeuser, Barbara</creatorcontrib><creatorcontrib>Albers, Michael</creatorcontrib><creatorcontrib>Sonnek, Christina</creatorcontrib><creatorcontrib>Wang, Yansong</creatorcontrib><creatorcontrib>Mallinger, Aurélie</creatorcontrib><creatorcontrib>Czekańska, Marta</creatorcontrib><creatorcontrib>Hoffmann, Thomas</creatorcontrib><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>Kinzel, Olaf</au><au>Steeneck, Christoph</au><au>Anderhub, Simon</au><au>Hornberger, Martin</au><au>Pinto, Sheena</au><au>Morschhaeuser, Barbara</au><au>Albers, Michael</au><au>Sonnek, Christina</au><au>Wang, Yansong</au><au>Mallinger, Aurélie</au><au>Czekańska, Marta</au><au>Hoffmann, Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2021-02-01</date><risdate>2021</risdate><volume>33</volume><spage>127738</spage><epage>127738</epage><pages>127738-127738</pages><artnum>127738</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1).</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33316404</pmid><doi>10.1016/j.bmcl.2020.127738</doi><tpages>1</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2021-02, Vol.33, p.127738-127738, Article 127738 |
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| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Cancer immunotherapy Heme-displacer IDO1 Indoleamine-2,3-dioxygenase-1 Spirofused Tryptophan-kynurenine-AhR-pathway |
| title | Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold |
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