Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)
The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.640-643 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | KAPLAN, Joshua VERHEIJEN, Jeroen C BROOIJMANS, Natasja TORAL-BARZA, Lourdes HOLLANDER, Irwin YU, Ker ZASK, Arie |
| description | The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2009.11.050 |
| format | Article |
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Drug treatments ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Pyrans - chemistry ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - pharmacology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; TOR Serine-Threonine Kinases</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-01, Vol.20 (2), p.640-643</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright 2009 Elsevier Ltd. 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Drug treatments</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Pyrans - chemistry</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>TOR Serine-Threonine Kinases</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV2L1DAYhYso7rj6B7yQ3IgKm5qvSRvvlvVjhYUVmQtBJKRpajMkTU0yC_VX-pNMnUHxKiQ878l5z6mqpxjVGGH-el93XruaICRqjGu0RfeqDWacQcrQ9n61QYIj2Ar25ax6lNIeIcwQYw-rMywEp7Rlm-rXW5t0uDNxAWEA9ILD3o5LHwMk13BeopqASkABH-I8BmcnA6KZndLGmykDOwEOVVwcxEf8Z3DhK71gsP9WrtbbvowUgakH5A-YR2umFSH_I2_A5e4T1MHPJtts70zRHm1nc4hptZZHA7zyXjlbPGUVv5u8vkc1K7_oYuSl391-fvW4ejAol8yT03le7d6_211dw5vbDx-vLm-gpqLNkDYN45rqnphmaEnJQxuskG4aYRBFqmt1R7qG43agWLcaEWR6pqjgmGw1oefVi6PsHMOPg0lZ-hKkcU5NJhySbEq8ghMuCkmOpI4hpWgGOZelSxQSI7n2KPdy7VGuPUqMZemxDD07yR86b_p_I6fiCvD8BKiklRtKUdqmvxwh5XvWtvQ38NGpiw</recordid><startdate>20100115</startdate><enddate>20100115</enddate><creator>KAPLAN, Joshua</creator><creator>VERHEIJEN, Jeroen C</creator><creator>BROOIJMANS, Natasja</creator><creator>TORAL-BARZA, Lourdes</creator><creator>HOLLANDER, Irwin</creator><creator>YU, Ker</creator><creator>ZASK, Arie</creator><general>Elsevier</general><scope>IQODW</scope><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>20100115</creationdate><title>Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)</title><author>KAPLAN, Joshua ; VERHEIJEN, Jeroen C ; BROOIJMANS, Natasja ; TORAL-BARZA, Lourdes ; HOLLANDER, Irwin ; YU, Ker ; ZASK, Arie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-37746c3cd2e7f82996ce1a0c779e030ab8cb2b7618f31c8c020ed4a396125c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenosine Triphosphate - chemistry</topic><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Computer Simulation</topic><topic>Drug Discovery</topic><topic>General aspects</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Microsomes - metabolism</topic><topic>Models, Molecular</topic><topic>Morpholines - chemistry</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Pyrans - chemistry</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>TOR Serine-Threonine Kinases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KAPLAN, Joshua</creatorcontrib><creatorcontrib>VERHEIJEN, Jeroen C</creatorcontrib><creatorcontrib>BROOIJMANS, Natasja</creatorcontrib><creatorcontrib>TORAL-BARZA, Lourdes</creatorcontrib><creatorcontrib>HOLLANDER, Irwin</creatorcontrib><creatorcontrib>YU, Ker</creatorcontrib><creatorcontrib>ZASK, Arie</creatorcontrib><collection>Pascal-Francis</collection><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>KAPLAN, Joshua</au><au>VERHEIJEN, Jeroen C</au><au>BROOIJMANS, Natasja</au><au>TORAL-BARZA, Lourdes</au><au>HOLLANDER, Irwin</au><au>YU, Ker</au><au>ZASK, Arie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-01-15</date><risdate>2010</risdate><volume>20</volume><issue>2</issue><spage>640</spage><epage>643</epage><pages>640-643</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. 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| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-01, Vol.20 (2), p.640-643 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Adenosine Triphosphate - chemistry Adenosine Triphosphate - metabolism Animals Antineoplastic agents Binding Sites Binding, Competitive Biological and medical sciences Computer Simulation Drug Discovery General aspects Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism Medical sciences Mice Microsomes - metabolism Models, Molecular Morpholines - chemistry Pharmacology. Drug treatments Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Pyrans - chemistry Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology TOR Serine-Threonine Kinases |
| title | Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR) |
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