Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable
The discovery and SAR of a novel class of imidazole-alkene-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro and in cells is reported. These compounds are lead-like with low molecular weight and good physical properties, and are orally bioavailable. Tie-2 is a receptor tyrosine kinase which...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-08, Vol.18 (16), p.4723-4726 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Buttar, David Edge, Mike Emery, Steve C. Fitzek, Martina Forder, Cheryl Griffen, Alison Hayter, Barry Hayward, Chris F. Hopcroft, Philip J. Luke, Richard W.A. Page, Ken Stawpert, John Wright, Andy |
| description | The discovery and SAR of a novel class of imidazole-alkene-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro and in cells is reported. These compounds are lead-like with low molecular weight and good physical properties, and are orally bioavailable.
Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability. |
| doi_str_mv | 10.1016/j.bmcl.2008.06.106 |
| format | Article |
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Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3405</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmcl.2008.06.106</identifier><identifier>PMID: 18676144</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Administration, Oral ; Alkene ; Angiogenesis ; Antineoplastic agents ; Biological and medical sciences ; Biological Availability ; Chemistry, Pharmaceutical - methods ; Drug Design ; General aspects ; Humans ; Imidazole ; Imidazoles - administration & dosage ; Imidazoles - chemical synthesis ; Inhibitor ; Inhibitory Concentration 50 ; Kinase ; Medical sciences ; Models, Chemical ; Molecular Conformation ; Neovascularization, Pathologic ; Pharmacology. Drug treatments ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacology ; Pyrimidine ; Pyrimidines - administration & dosage ; Pyrimidines - chemical synthesis ; Pyrimidines - pharmacology ; Receptor, TIE-2 - antagonists & inhibitors ; Receptor, TIE-2 - chemistry ; Structure-Activity Relationship ; Tie-2</subject><ispartof>Bioorganic & medicinal chemistry, 2008-08, Vol.18 (16), p.4723-4726</ispartof><rights>2008 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-46d074a731bea1ac974653fa2e7e71595ed6d63fe1cb81cc6b787eeb16b8b81f3</citedby><cites>FETCH-LOGICAL-c415t-46d074a731bea1ac974653fa2e7e71595ed6d63fe1cb81cc6b787eeb16b8b81f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2008.06.106$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20608635$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18676144$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Buttar, David</creatorcontrib><creatorcontrib>Edge, Mike</creatorcontrib><creatorcontrib>Emery, Steve C.</creatorcontrib><creatorcontrib>Fitzek, Martina</creatorcontrib><creatorcontrib>Forder, Cheryl</creatorcontrib><creatorcontrib>Griffen, Alison</creatorcontrib><creatorcontrib>Hayter, Barry</creatorcontrib><creatorcontrib>Hayward, Chris F.</creatorcontrib><creatorcontrib>Hopcroft, Philip J.</creatorcontrib><creatorcontrib>Luke, Richard W.A.</creatorcontrib><creatorcontrib>Page, Ken</creatorcontrib><creatorcontrib>Stawpert, John</creatorcontrib><creatorcontrib>Wright, Andy</creatorcontrib><title>Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The discovery and SAR of a novel class of imidazole-alkene-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro and in cells is reported. These compounds are lead-like with low molecular weight and good physical properties, and are orally bioavailable.
Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.</description><subject>Administration, Oral</subject><subject>Alkene</subject><subject>Angiogenesis</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Drug Design</subject><subject>General aspects</subject><subject>Humans</subject><subject>Imidazole</subject><subject>Imidazoles - administration & dosage</subject><subject>Imidazoles - chemical synthesis</subject><subject>Inhibitor</subject><subject>Inhibitory Concentration 50</subject><subject>Kinase</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Molecular Conformation</subject><subject>Neovascularization, Pathologic</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrimidine</subject><subject>Pyrimidines - administration & dosage</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptor, TIE-2 - antagonists & inhibitors</subject><subject>Receptor, TIE-2 - chemistry</subject><subject>Structure-Activity Relationship</subject><subject>Tie-2</subject><issn>0960-894X</issn><issn>0968-0896</issn><issn>1464-3405</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE2LFDEQQIMo7rj6BzxILnrrMelOJ93gRXb9ggUvK3gLlXQ1U2OmMyYzI-3B326aGfUmBAKPV0XyGHsuxVoKqV9v127nw7oWolsLXZh-wFZSaVU1SrQP2Ur0WlRdr75esSc5b4WQSij1mF3JThstlVqxX7eUfTxhmnkcOe1ogJ8xID_RNAe-n9OCaMLMoRw-FTVwHyDnxf9GE2TkNG3I0SGmzH9syG_-AH5PWNUcpoFDQh4ThDBzRxFOQAFcwKfs0Qgh47PLfc2-vH93f_Oxuvv84dPN27vKK9keKqUHYRSYRjoECb43SrfNCDUaNLLtWxz0oJsRpXed9F470xlEJ7XrChiba_bqvHef4vcj5oPdlX9jCDBhPGYreyNN2-oi1mfRp5hzwtHuSwJIs5XCLtXt1i7V7VLdCl3YMvTisv3odjj8G7lkLsLLiwDZQxgTTJ7yX68WWnS6aYv35uxhaXEiTDZ7wsnjQAn9wQ6R_veO38ZlopM</recordid><startdate>20080815</startdate><enddate>20080815</enddate><creator>Buttar, David</creator><creator>Edge, Mike</creator><creator>Emery, Steve C.</creator><creator>Fitzek, Martina</creator><creator>Forder, Cheryl</creator><creator>Griffen, Alison</creator><creator>Hayter, Barry</creator><creator>Hayward, Chris F.</creator><creator>Hopcroft, Philip J.</creator><creator>Luke, Richard W.A.</creator><creator>Page, Ken</creator><creator>Stawpert, John</creator><creator>Wright, Andy</creator><general>Elsevier Ltd</general><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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20080815</creationdate><title>Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable</title><author>Buttar, David ; Edge, Mike ; Emery, Steve C. ; Fitzek, Martina ; Forder, Cheryl ; Griffen, Alison ; Hayter, Barry ; Hayward, Chris F. ; Hopcroft, Philip J. ; Luke, Richard W.A. ; Page, Ken ; Stawpert, John ; Wright, Andy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-46d074a731bea1ac974653fa2e7e71595ed6d63fe1cb81cc6b787eeb16b8b81f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Administration, Oral</topic><topic>Alkene</topic><topic>Angiogenesis</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Drug Design</topic><topic>General aspects</topic><topic>Humans</topic><topic>Imidazole</topic><topic>Imidazoles - administration & dosage</topic><topic>Imidazoles - chemical synthesis</topic><topic>Inhibitor</topic><topic>Inhibitory Concentration 50</topic><topic>Kinase</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Molecular Conformation</topic><topic>Neovascularization, Pathologic</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Kinase Inhibitors - administration & dosage</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrimidine</topic><topic>Pyrimidines - administration & dosage</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptor, TIE-2 - antagonists & inhibitors</topic><topic>Receptor, TIE-2 - chemistry</topic><topic>Structure-Activity Relationship</topic><topic>Tie-2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Buttar, David</creatorcontrib><creatorcontrib>Edge, Mike</creatorcontrib><creatorcontrib>Emery, Steve C.</creatorcontrib><creatorcontrib>Fitzek, Martina</creatorcontrib><creatorcontrib>Forder, Cheryl</creatorcontrib><creatorcontrib>Griffen, Alison</creatorcontrib><creatorcontrib>Hayter, Barry</creatorcontrib><creatorcontrib>Hayward, Chris F.</creatorcontrib><creatorcontrib>Hopcroft, Philip J.</creatorcontrib><creatorcontrib>Luke, Richard W.A.</creatorcontrib><creatorcontrib>Page, Ken</creatorcontrib><creatorcontrib>Stawpert, John</creatorcontrib><creatorcontrib>Wright, Andy</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>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Buttar, David</au><au>Edge, Mike</au><au>Emery, Steve C.</au><au>Fitzek, Martina</au><au>Forder, Cheryl</au><au>Griffen, Alison</au><au>Hayter, Barry</au><au>Hayward, Chris F.</au><au>Hopcroft, Philip J.</au><au>Luke, Richard W.A.</au><au>Page, Ken</au><au>Stawpert, John</au><au>Wright, Andy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2008-08-15</date><risdate>2008</risdate><volume>18</volume><issue>16</issue><spage>4723</spage><epage>4726</epage><pages>4723-4726</pages><issn>0960-894X</issn><issn>0968-0896</issn><eissn>1464-3405</eissn><eissn>1464-3391</eissn><abstract>The discovery and SAR of a novel class of imidazole-alkene-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro and in cells is reported. These compounds are lead-like with low molecular weight and good physical properties, and are orally bioavailable.
Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>18676144</pmid><doi>10.1016/j.bmcl.2008.06.106</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry, 2008-08, Vol.18 (16), p.4723-4726 |
| issn | 0960-894X 0968-0896 1464-3405 1464-3391 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Alkene Angiogenesis Antineoplastic agents Biological and medical sciences Biological Availability Chemistry, Pharmaceutical - methods Drug Design General aspects Humans Imidazole Imidazoles - administration & dosage Imidazoles - chemical synthesis Inhibitor Inhibitory Concentration 50 Kinase Medical sciences Models, Chemical Molecular Conformation Neovascularization, Pathologic Pharmacology. Drug treatments Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Pyrimidine Pyrimidines - administration & dosage Pyrimidines - chemical synthesis Pyrimidines - pharmacology Receptor, TIE-2 - antagonists & inhibitors Receptor, TIE-2 - chemistry Structure-Activity Relationship Tie-2 |
| title | Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable |
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