Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties
[Display omitted] In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP rang...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-12, Vol.26 (23), p.5657-5662 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Hoegenauer, Klemens Soldermann, Nicolas Hebach, Christina Hollingworth, Gregory J. Lewis, Ian von Matt, Anette Smith, Alexander B. Wolf, Romain M. Wilcken, Rainer Haasen, Dorothea Burkhart, Christoph Zécri, Frédéric |
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In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate. |
| doi_str_mv | 10.1016/j.bmcl.2016.10.069 |
| format | Article |
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In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.10.069</identifier><identifier>PMID: 27816514</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Drug Discovery - methods ; Drug Evaluation, Preclinical - methods ; Enzyme Assays - methods ; Humans ; Lipophilicity ; Mice ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3-kinase delta inhibitor ; Physicochemical properties ; PI3Kδ inhibitor ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Pyrrolidines - chemistry ; Pyrrolidines - pharmacology ; Quinazolines - chemistry ; Quinazolines - pharmacology ; Rats ; Structure-activity relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-12, Vol.26 (23), p.5657-5662</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-c356t-996548adbabb2ca8b857a50dc5871e6b1b379c6e382082ce4063c627ebd37083</citedby><cites>FETCH-LOGICAL-c356t-996548adbabb2ca8b857a50dc5871e6b1b379c6e382082ce4063c627ebd37083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X16311064$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27816514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hoegenauer, Klemens</creatorcontrib><creatorcontrib>Soldermann, Nicolas</creatorcontrib><creatorcontrib>Hebach, Christina</creatorcontrib><creatorcontrib>Hollingworth, Gregory J.</creatorcontrib><creatorcontrib>Lewis, Ian</creatorcontrib><creatorcontrib>von Matt, Anette</creatorcontrib><creatorcontrib>Smith, Alexander B.</creatorcontrib><creatorcontrib>Wolf, Romain M.</creatorcontrib><creatorcontrib>Wilcken, Rainer</creatorcontrib><creatorcontrib>Haasen, Dorothea</creatorcontrib><creatorcontrib>Burkhart, Christoph</creatorcontrib><creatorcontrib>Zécri, Frédéric</creatorcontrib><title>Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.</description><subject>Animals</subject><subject>Drug Discovery - methods</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Enzyme Assays - methods</subject><subject>Humans</subject><subject>Lipophilicity</subject><subject>Mice</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3-kinase delta inhibitor</subject><subject>Physicochemical properties</subject><subject>PI3Kδ inhibitor</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - pharmacology</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</subject><subject>Rats</subject><subject>Structure-activity relationship</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>eNp9UcuO1DAQtBCIHRZ-gAPykUsGO3EcR-KClteKleCwB26WHz1Kj5I42M5A_oMPxqNZOHLqVqu6SlVFyEvO9pxx-ea4t5Mb93XZy2HPZP-I7LiQomoEax-THeslq1Qvvl-RZykdGeOCCfGUXNWd4rLlYkd-v8fkwgniRsOBzmUb6bLFGEb0OEP4tVVptSljXjN4OkCGGEwMk8noEjWJLiHDnKmZPU0wgst4AvrttvlCPYzZUJwHtJhDTPQn5oHitMQi4-kybAldcANM6EyRjWGBmBHSc_LkYMYELx7mNbn_-OH-5nN19_XT7c27u8o1rcxV38tWKOOtsbZ2RlnVdqZl3rWq4yAtt03XOwmNqpmqHQgmGyfrDqxvOqaaa_L6QluUf6yQsp5KGDCOphhfk-aqwOq25U2B1heoiyGlCAe9RJxM3DRn-lyGPupzGfpcxvlWyihPrx74VzuB__fyN_0CeHsBQDF5Qog6OYTZgcdYgtQ-4P_4_wDoOp_g</recordid><startdate>20161201</startdate><enddate>20161201</enddate><creator>Hoegenauer, Klemens</creator><creator>Soldermann, Nicolas</creator><creator>Hebach, Christina</creator><creator>Hollingworth, Gregory J.</creator><creator>Lewis, Ian</creator><creator>von Matt, Anette</creator><creator>Smith, Alexander B.</creator><creator>Wolf, Romain M.</creator><creator>Wilcken, Rainer</creator><creator>Haasen, Dorothea</creator><creator>Burkhart, Christoph</creator><creator>Zécri, Frédéric</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>20161201</creationdate><title>Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties</title><author>Hoegenauer, Klemens ; Soldermann, Nicolas ; Hebach, Christina ; Hollingworth, Gregory J. ; Lewis, Ian ; von Matt, Anette ; Smith, Alexander B. ; Wolf, Romain M. ; Wilcken, Rainer ; Haasen, Dorothea ; Burkhart, Christoph ; Zécri, Frédéric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-996548adbabb2ca8b857a50dc5871e6b1b379c6e382082ce4063c627ebd37083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Drug Discovery - methods</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Enzyme Assays - methods</topic><topic>Humans</topic><topic>Lipophilicity</topic><topic>Mice</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3-kinase delta inhibitor</topic><topic>Physicochemical properties</topic><topic>PI3Kδ inhibitor</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrrolidines - chemistry</topic><topic>Pyrrolidines - pharmacology</topic><topic>Quinazolines - chemistry</topic><topic>Quinazolines - pharmacology</topic><topic>Rats</topic><topic>Structure-activity relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hoegenauer, Klemens</creatorcontrib><creatorcontrib>Soldermann, Nicolas</creatorcontrib><creatorcontrib>Hebach, Christina</creatorcontrib><creatorcontrib>Hollingworth, Gregory J.</creatorcontrib><creatorcontrib>Lewis, Ian</creatorcontrib><creatorcontrib>von Matt, Anette</creatorcontrib><creatorcontrib>Smith, Alexander B.</creatorcontrib><creatorcontrib>Wolf, Romain M.</creatorcontrib><creatorcontrib>Wilcken, Rainer</creatorcontrib><creatorcontrib>Haasen, Dorothea</creatorcontrib><creatorcontrib>Burkhart, Christoph</creatorcontrib><creatorcontrib>Zécri, Frédéric</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>Hoegenauer, Klemens</au><au>Soldermann, Nicolas</au><au>Hebach, Christina</au><au>Hollingworth, Gregory J.</au><au>Lewis, Ian</au><au>von Matt, Anette</au><au>Smith, Alexander B.</au><au>Wolf, Romain M.</au><au>Wilcken, Rainer</au><au>Haasen, Dorothea</au><au>Burkhart, Christoph</au><au>Zécri, Frédéric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-12-01</date><risdate>2016</risdate><volume>26</volume><issue>23</issue><spage>5657</spage><epage>5662</epage><pages>5657-5662</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27816514</pmid><doi>10.1016/j.bmcl.2016.10.069</doi><tpages>6</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2016-12, Vol.26 (23), p.5657-5662 |
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| subjects | Animals Drug Discovery - methods Drug Evaluation, Preclinical - methods Enzyme Assays - methods Humans Lipophilicity Mice Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3-kinase delta inhibitor Physicochemical properties PI3Kδ inhibitor Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrrolidines - chemistry Pyrrolidines - pharmacology Quinazolines - chemistry Quinazolines - pharmacology Rats Structure-activity relationship |
| title | Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties |
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