Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy
[Display omitted] The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-06, Vol.27 (11), p.2536-2543 |
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| creator | Martínez González, Sonia Rodríguez-Arístegui, Sonsoles Hernández, Ana Isabel Varela, Carmen González Cantalapiedra, Esther Álvarez, Rosa María Rodríguez Hergueta, Antonio Bischoff, James R. Albarrán, María Isabel Cebriá, Antonio Cendón, Elena Cebrián, David Alfonso, Patricia Pastor, Joaquín |
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The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al., 2012)1 by the application of a conformational restriction strategy. For that purpose we have successfully synthesized novel tricyclic imidazo[1,2-a]pyrazine derivatives as PI3K inhibitors. This new class of compounds had enable the exploration of the solvent-accessible region within PI3K and resulted in the identification of molecule 8q with the best selectivity PI3Kα/δ isoform profile in vitro, and promising in vivo PK data. |
| doi_str_mv | 10.1016/j.bmcl.2017.03.090 |
| format | Article |
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The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al., 2012)1 by the application of a conformational restriction strategy. For that purpose we have successfully synthesized novel tricyclic imidazo[1,2-a]pyrazine derivatives as PI3K inhibitors. This new class of compounds had enable the exploration of the solvent-accessible region within PI3K and resulted in the identification of molecule 8q with the best selectivity PI3Kα/δ isoform profile in vitro, and promising in vivo PK data.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.03.090</identifier><identifier>PMID: 28404374</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Cancer treatment ; Conformational restriction ; ETP-46321 ; Half-Life ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacokinetics ; Inhibitory Concentration 50 ; Mice ; Microsomes, Liver - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - metabolism ; PI3K inhibitors ; Protein Isoforms - antagonists & inhibitors ; Protein Isoforms - metabolism ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacokinetics ; Pyrazines - chemical synthesis ; Pyrazines - chemistry ; Pyrazines - pharmacokinetics ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-06, Vol.27 (11), p.2536-2543</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-c356t-beebfe593f65f496c17ff67fc28a9a849e62643078e951b887222f55f79e9b103</citedby><cites>FETCH-LOGICAL-c356t-beebfe593f65f496c17ff67fc28a9a849e62643078e951b887222f55f79e9b103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X17303402$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28404374$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martínez González, Sonia</creatorcontrib><creatorcontrib>Rodríguez-Arístegui, Sonsoles</creatorcontrib><creatorcontrib>Hernández, Ana Isabel</creatorcontrib><creatorcontrib>Varela, Carmen</creatorcontrib><creatorcontrib>González Cantalapiedra, Esther</creatorcontrib><creatorcontrib>Álvarez, Rosa María</creatorcontrib><creatorcontrib>Rodríguez Hergueta, Antonio</creatorcontrib><creatorcontrib>Bischoff, James R.</creatorcontrib><creatorcontrib>Albarrán, María Isabel</creatorcontrib><creatorcontrib>Cebriá, Antonio</creatorcontrib><creatorcontrib>Cendón, Elena</creatorcontrib><creatorcontrib>Cebrián, David</creatorcontrib><creatorcontrib>Alfonso, Patricia</creatorcontrib><creatorcontrib>Pastor, Joaquín</creatorcontrib><title>Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al., 2012)1 by the application of a conformational restriction strategy. For that purpose we have successfully synthesized novel tricyclic imidazo[1,2-a]pyrazine derivatives as PI3K inhibitors. This new class of compounds had enable the exploration of the solvent-accessible region within PI3K and resulted in the identification of molecule 8q with the best selectivity PI3Kα/δ isoform profile in vitro, and promising in vivo PK data.</description><subject>Animals</subject><subject>Cancer treatment</subject><subject>Conformational restriction</subject><subject>ETP-46321</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacokinetics</subject><subject>Inhibitory Concentration 50</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>PI3K inhibitors</subject><subject>Protein Isoforms - antagonists & inhibitors</subject><subject>Protein Isoforms - metabolism</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Pyrazines - chemical synthesis</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacokinetics</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1O3DAUhS3UCgbaF2CBvOyiCf6LE0tsKlQoKlJZUAkJVZbjuQaPkjjYGaSw4tHxMMCyKx_Z55x7_SF0SElJCZXHq7LtbVcyQuuS8JIosoMWVEhRcEGqT2hBlCRFo8TNHtpPaUUIFUSIXbTHmix4LRbo-RwGiGbyYcDB4Sl6O9vOW-x7vzRP4ZZ-Z4X5N87RPPkBEjYJD-EROnx1wX9jP9z71k8hJtzO2Ixjjn6UGWzD4ELsX29MhyOkzYDX96zMBHfzF_TZmS7B17fzAP09-3l9-qu4_HN-cfrjsrC8klPRArQOKsWdrJxQ0tLaOVk7yxqjTCMUSCYFJ3UDqqJt09SMMVdVrlagWkr4Afq27R1jeFjnRXTvk4WuMwOEddI0RwSrG8azlW2tNoaUIjg9Rt-bOGtK9Ia8XukNeb0hrwnXmXwOHb31r9selh-Rd9TZcLI1QP7lo4eok_UwWFj6CHbSy-D_1_8CwRGWyg</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Martínez González, Sonia</creator><creator>Rodríguez-Arístegui, Sonsoles</creator><creator>Hernández, Ana Isabel</creator><creator>Varela, Carmen</creator><creator>González Cantalapiedra, Esther</creator><creator>Álvarez, Rosa María</creator><creator>Rodríguez Hergueta, Antonio</creator><creator>Bischoff, James R.</creator><creator>Albarrán, María Isabel</creator><creator>Cebriá, Antonio</creator><creator>Cendón, Elena</creator><creator>Cebrián, David</creator><creator>Alfonso, Patricia</creator><creator>Pastor, Joaquín</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>20170601</creationdate><title>Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy</title><author>Martínez González, Sonia ; Rodríguez-Arístegui, Sonsoles ; Hernández, Ana Isabel ; Varela, Carmen ; González Cantalapiedra, Esther ; Álvarez, Rosa María ; Rodríguez Hergueta, Antonio ; Bischoff, James R. ; Albarrán, María Isabel ; Cebriá, Antonio ; Cendón, Elena ; Cebrián, David ; Alfonso, Patricia ; Pastor, Joaquín</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-beebfe593f65f496c17ff67fc28a9a849e62643078e951b887222f55f79e9b103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Cancer treatment</topic><topic>Conformational restriction</topic><topic>ETP-46321</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacokinetics</topic><topic>Inhibitory Concentration 50</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>PI3K inhibitors</topic><topic>Protein Isoforms - antagonists & inhibitors</topic><topic>Protein Isoforms - metabolism</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Pyrazines - chemical synthesis</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacokinetics</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martínez González, Sonia</creatorcontrib><creatorcontrib>Rodríguez-Arístegui, Sonsoles</creatorcontrib><creatorcontrib>Hernández, Ana Isabel</creatorcontrib><creatorcontrib>Varela, Carmen</creatorcontrib><creatorcontrib>González Cantalapiedra, Esther</creatorcontrib><creatorcontrib>Álvarez, Rosa María</creatorcontrib><creatorcontrib>Rodríguez Hergueta, Antonio</creatorcontrib><creatorcontrib>Bischoff, James R.</creatorcontrib><creatorcontrib>Albarrán, María Isabel</creatorcontrib><creatorcontrib>Cebriá, Antonio</creatorcontrib><creatorcontrib>Cendón, Elena</creatorcontrib><creatorcontrib>Cebrián, David</creatorcontrib><creatorcontrib>Alfonso, Patricia</creatorcontrib><creatorcontrib>Pastor, Joaquín</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>Martínez González, Sonia</au><au>Rodríguez-Arístegui, Sonsoles</au><au>Hernández, Ana Isabel</au><au>Varela, Carmen</au><au>González Cantalapiedra, Esther</au><au>Álvarez, Rosa María</au><au>Rodríguez Hergueta, Antonio</au><au>Bischoff, James R.</au><au>Albarrán, María Isabel</au><au>Cebriá, Antonio</au><au>Cendón, Elena</au><au>Cebrián, David</au><au>Alfonso, Patricia</au><au>Pastor, Joaquín</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>27</volume><issue>11</issue><spage>2536</spage><epage>2543</epage><pages>2536-2543</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The involvement of the phosphoinositide 3-kinases (PI3Ks) in several diseases, especially in the oncology area, has singled it as one of the most explored therapeutic targets in the last two decades. Many different inhibitor classes have been developed by the industry and academia with a diverse selectivity profile within the PI3K family. In the present manuscript we report a further exploration of our lead PI3K inhibitor ETP-46321 (Martínez González et al., 2012)1 by the application of a conformational restriction strategy. For that purpose we have successfully synthesized novel tricyclic imidazo[1,2-a]pyrazine derivatives as PI3K inhibitors. This new class of compounds had enable the exploration of the solvent-accessible region within PI3K and resulted in the identification of molecule 8q with the best selectivity PI3Kα/δ isoform profile in vitro, and promising in vivo PK data.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28404374</pmid><doi>10.1016/j.bmcl.2017.03.090</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-06, Vol.27 (11), p.2536-2543 |
| issn | 0960-894X 1464-3405 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Cancer treatment Conformational restriction ETP-46321 Half-Life Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacokinetics Inhibitory Concentration 50 Mice Microsomes, Liver - metabolism Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism PI3K inhibitors Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacokinetics Structure-Activity Relationship |
| title | Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy |
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