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Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors
A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are describ...
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| Published in: | Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2230-2234 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c441t-106c4b02bb1e0bf54310027fc63303d3ea66051ab6a83508fca7c0152a0e4f83 |
| container_end_page | 2234 |
| container_issue | 6 |
| container_start_page | 2230 |
| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lin, Hong Erhard, Karl Hardwicke, Mary Ann Luengo, Juan I. Mack, James F. McSurdy-Freed, Jeanelle Plant, Ramona Raha, Kaushik Rominger, Cynthia M. Sanchez, Robert M. Schaber, Michael D. Schulz, Mark J. Spengler, Michael D. Tedesco, Rosanna Xie, Ren Zeng, Jin J. Rivero, Ralph A. |
| description | A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions. |
| doi_str_mv | 10.1016/j.bmcl.2012.01.092 |
| format | article |
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Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2012.01.092</identifier><identifier>PMID: 22361133</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Binding Sites ; Biological and medical sciences ; Breast Neoplasms ; Cell Line, Tumor ; chemotypes ; Drug Screening Assays, Antitumor ; enantiomers ; Female ; Gene Deletion ; Homology model ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - pharmacology ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Kinetics ; Medical sciences ; Models, Molecular ; Pharmacology. Drug treatments ; Phosphatidylinositol 3-kinase ; Phosphatidylinositol 3-Kinase - antagonists & inhibitors ; Phosphatidylinositol 3-Kinase - metabolism ; PI3K-beta inhibitor ; Protein Binding ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacology ; PTEN Phosphohydrolase - deficiency ; PTEN Phosphohydrolase - genetics ; PTEN-null ; Pyrimidinones - chemical synthesis ; Pyrimidinones - pharmacology ; Structure-Activity Relationship ; structure-activity relationships</subject><ispartof>Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (6), p.2230-2234</ispartof><rights>2012 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-106c4b02bb1e0bf54310027fc63303d3ea66051ab6a83508fca7c0152a0e4f83</citedby><cites>FETCH-LOGICAL-c441t-106c4b02bb1e0bf54310027fc63303d3ea66051ab6a83508fca7c0152a0e4f83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25696945$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22361133$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Hong</creatorcontrib><creatorcontrib>Erhard, Karl</creatorcontrib><creatorcontrib>Hardwicke, Mary Ann</creatorcontrib><creatorcontrib>Luengo, Juan I.</creatorcontrib><creatorcontrib>Mack, James F.</creatorcontrib><creatorcontrib>McSurdy-Freed, Jeanelle</creatorcontrib><creatorcontrib>Plant, Ramona</creatorcontrib><creatorcontrib>Raha, Kaushik</creatorcontrib><creatorcontrib>Rominger, Cynthia M.</creatorcontrib><creatorcontrib>Sanchez, Robert M.</creatorcontrib><creatorcontrib>Schaber, Michael D.</creatorcontrib><creatorcontrib>Schulz, Mark J.</creatorcontrib><creatorcontrib>Spengler, Michael D.</creatorcontrib><creatorcontrib>Tedesco, Rosanna</creatorcontrib><creatorcontrib>Xie, Ren</creatorcontrib><creatorcontrib>Zeng, Jin J.</creatorcontrib><creatorcontrib>Rivero, Ralph A.</creatorcontrib><title>Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms</subject><subject>Cell Line, Tumor</subject><subject>chemotypes</subject><subject>Drug Screening Assays, Antitumor</subject><subject>enantiomers</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>Homology model</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - pharmacology</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphatidylinositol 3-kinase</subject><subject>Phosphatidylinositol 3-Kinase - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>PI3K-beta inhibitor</subject><subject>Protein Binding</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>PTEN Phosphohydrolase - deficiency</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN-null</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNqNkt-K1DAUxoso7rj6Al5ob0QFO578aaYFb2RRV1jwYlcQREKanjoZO0nNaQfGK9_Bx_CtfBJTZ9Q7EQKBw-_7vnC-ZNldBksGTD3dLJut7ZccGF8CW0LNr2ULJpUshITyeraAWkFR1fLdSXaLaAPAJEh5MzvhXCjGhFhk3y_3flwjOcqNb3Ma42THKeKPr9-MHd3Ojfs8Ym9GFzyt3UB56HK3da35Et6zJ7wwH4Z9nAfOF-Ujdv64CB6TWTq5Dzvsc8Lo8JeuwdHkjkIX4jaNe5wTMB_WgYZ1imj3vfOB3Bj6XBSfnDeEufNr16RRpNvZjc70hHeO92l29fLF1dl5cfHm1euz5xeFlZKNBQNlZQO8aRhC05VSMAC-6qwSAkQr0CgFJTONMpUooeqsWVlgJTeAsqvEafbwYDvE8HlCGvXWkcW-Nx7DRLpWFVOVrP6D5KqEFVvxRPIDaWMgitjpIS3NxL1moOcy9UbPZeq5TA1MpzKT6N7Rfmq22P6R_G4vAQ-OgCFr-i4abx395UpVq1qWibt_4DoTtPkYE_P2MiWV6UfMVnPUswOBaa87h1GTdegtti6mlnQb3L9e-hNoUspH</recordid><startdate>20120315</startdate><enddate>20120315</enddate><creator>Lin, Hong</creator><creator>Erhard, Karl</creator><creator>Hardwicke, Mary Ann</creator><creator>Luengo, Juan I.</creator><creator>Mack, James F.</creator><creator>McSurdy-Freed, Jeanelle</creator><creator>Plant, Ramona</creator><creator>Raha, Kaushik</creator><creator>Rominger, Cynthia M.</creator><creator>Sanchez, Robert M.</creator><creator>Schaber, Michael D.</creator><creator>Schulz, Mark J.</creator><creator>Spengler, Michael D.</creator><creator>Tedesco, Rosanna</creator><creator>Xie, Ren</creator><creator>Zeng, Jin J.</creator><creator>Rivero, Ralph A.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20120315</creationdate><title>Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors</title><author>Lin, Hong ; Erhard, Karl ; Hardwicke, Mary Ann ; Luengo, Juan I. ; Mack, James F. ; McSurdy-Freed, Jeanelle ; Plant, Ramona ; Raha, Kaushik ; Rominger, Cynthia M. ; Sanchez, Robert M. ; Schaber, Michael D. ; Schulz, Mark J. ; Spengler, Michael D. ; Tedesco, Rosanna ; Xie, Ren ; Zeng, Jin J. ; Rivero, Ralph A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-106c4b02bb1e0bf54310027fc63303d3ea66051ab6a83508fca7c0152a0e4f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms</topic><topic>Cell Line, Tumor</topic><topic>chemotypes</topic><topic>Drug Screening Assays, Antitumor</topic><topic>enantiomers</topic><topic>Female</topic><topic>Gene Deletion</topic><topic>Homology model</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - pharmacology</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Isoenzymes - metabolism</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphatidylinositol 3-kinase</topic><topic>Phosphatidylinositol 3-Kinase - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinase - metabolism</topic><topic>PI3K-beta inhibitor</topic><topic>Protein Binding</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>PTEN Phosphohydrolase - deficiency</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>PTEN-null</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>structure-activity relationships</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Hong</creatorcontrib><creatorcontrib>Erhard, Karl</creatorcontrib><creatorcontrib>Hardwicke, Mary Ann</creatorcontrib><creatorcontrib>Luengo, Juan I.</creatorcontrib><creatorcontrib>Mack, James F.</creatorcontrib><creatorcontrib>McSurdy-Freed, Jeanelle</creatorcontrib><creatorcontrib>Plant, Ramona</creatorcontrib><creatorcontrib>Raha, Kaushik</creatorcontrib><creatorcontrib>Rominger, Cynthia M.</creatorcontrib><creatorcontrib>Sanchez, Robert M.</creatorcontrib><creatorcontrib>Schaber, Michael D.</creatorcontrib><creatorcontrib>Schulz, Mark J.</creatorcontrib><creatorcontrib>Spengler, Michael D.</creatorcontrib><creatorcontrib>Tedesco, Rosanna</creatorcontrib><creatorcontrib>Xie, Ren</creatorcontrib><creatorcontrib>Zeng, Jin J.</creatorcontrib><creatorcontrib>Rivero, Ralph A.</creatorcontrib><collection>AGRIS</collection><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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Hong</au><au>Erhard, Karl</au><au>Hardwicke, Mary Ann</au><au>Luengo, Juan I.</au><au>Mack, James F.</au><au>McSurdy-Freed, Jeanelle</au><au>Plant, Ramona</au><au>Raha, Kaushik</au><au>Rominger, Cynthia M.</au><au>Sanchez, Robert M.</au><au>Schaber, Michael D.</au><au>Schulz, Mark J.</au><au>Spengler, Michael D.</au><au>Tedesco, Rosanna</au><au>Xie, Ren</au><au>Zeng, Jin J.</au><au>Rivero, Ralph A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2012-03-15</date><risdate>2012</risdate><volume>22</volume><issue>6</issue><spage>2230</spage><epage>2234</epage><pages>2230-2234</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>22361133</pmid><doi>10.1016/j.bmcl.2012.01.092</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-03, Vol.22 (6), p.2230-2234 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | Elsevier |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Binding Sites Biological and medical sciences Breast Neoplasms Cell Line, Tumor chemotypes Drug Screening Assays, Antitumor enantiomers Female Gene Deletion Homology model Humans Imidazoles - chemical synthesis Imidazoles - pharmacology Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Kinetics Medical sciences Models, Molecular Pharmacology. Drug treatments Phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinase - antagonists & inhibitors Phosphatidylinositol 3-Kinase - metabolism PI3K-beta inhibitor Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology PTEN Phosphohydrolase - deficiency PTEN Phosphohydrolase - genetics PTEN-null Pyrimidinones - chemical synthesis Pyrimidinones - pharmacology Structure-Activity Relationship structure-activity relationships |
| title | Synthesis and structure–activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors |
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