Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke
We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimetho...
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| Veröffentlicht in: | Chemical & Pharmaceutical Bulletin 2007, Vol.55(6), pp.881-889 |
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| creator | Mukaiyama, Harunobu Nishimura, Toshihiro Shiohara, Hiroaki Kobayashi, Satoko Komatsu, Yoshimitsu Kikuchi, Shinji Tsuji, Eiichi Kamada, Noboru Ohnota, Hideki Kusama, Hiroshi |
| description | We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f·HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally. |
| doi_str_mv | 10.1248/cpb.55.881 |
| format | Article |
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Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f·HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.55.881</identifier><identifier>PMID: 17541186</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>acute ischemic stroke ; Animals ; c-Src kinase ; central nervous system penetration ; Crystallography, X-Ray ; Magnetic Resonance Spectroscopy ; Male ; Models, Molecular ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - therapeutic use ; pyrazolo[1,5-a]pyrimidine ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Spectrophotometry, Infrared ; src-Family Kinases - antagonists & inhibitors ; Stroke - drug therapy</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2007, Vol.55(6), pp.881-889</ispartof><rights>2007 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c690t-8ace6466dfbc99dcc64069c1dfb318b70275490c1c1305d605349ba09b057a83</citedby><cites>FETCH-LOGICAL-c690t-8ace6466dfbc99dcc64069c1dfb318b70275490c1c1305d605349ba09b057a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,1884,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17541186$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mukaiyama, Harunobu</creatorcontrib><creatorcontrib>Nishimura, Toshihiro</creatorcontrib><creatorcontrib>Shiohara, Hiroaki</creatorcontrib><creatorcontrib>Kobayashi, Satoko</creatorcontrib><creatorcontrib>Komatsu, Yoshimitsu</creatorcontrib><creatorcontrib>Kikuchi, Shinji</creatorcontrib><creatorcontrib>Tsuji, Eiichi</creatorcontrib><creatorcontrib>Kamada, Noboru</creatorcontrib><creatorcontrib>Ohnota, Hideki</creatorcontrib><creatorcontrib>Kusama, Hiroshi</creatorcontrib><creatorcontrib>Central Research Laboratory</creatorcontrib><creatorcontrib>Kissei Pharmaceutical Company Ltd</creatorcontrib><title>Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke</title><title>Chemical & Pharmaceutical Bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f·HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.</description><subject>acute ischemic stroke</subject><subject>Animals</subject><subject>c-Src kinase</subject><subject>central nervous system penetration</subject><subject>Crystallography, X-Ray</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Models, Molecular</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>pyrazolo[1,5-a]pyrimidine</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spectrophotometry, Infrared</subject><subject>src-Family Kinases - antagonists & inhibitors</subject><subject>Stroke - drug therapy</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEQxy0EoqFw4QGQJSQOiA3j9dq7PqGoH1BRwaG5IWR5nQlx2KyD7UQKL9DXxtsNrcSFy3hG8_N8_Ql5yWDKyqp5b7ftVIhp07BHZMJ4VReiLPljMgEAVZRc8hPyLMY1QCmg5k_JCatFxVgjJ-T23EXr9xgO1C_pl-x1tCxmvetc77eHYH77zn9j70RhvufQbdzC9UjPMbi9SW6PkZpIbXETLP3sehORXvUr17rkQ6RLH2haIZ0HNGmDfRqazOwuZSraFW6cpTcp-J_4nDxZmi7ii-N7SuaXF_OzT8X1149XZ7PrwkoFqWiMRVlJuVi2VqmFtbICqSzLMWdNW0OZN1NgmWUcxEKC4JVqDagWRG0afkrejGW3wf_aYUx6k_fHrjM9-l3UNeTDcGD_BZmqS1EDZPD1P-Da70Kfd9CsklDlCZTM1NuRssHHGHCpt_mWJhw0Az2IqLOIWgidRczwq2PJXbvBxQN6VC0DlyOQs86azvdZLXxobGN9d1xdAtQaQAiQ-s7N5QejBC9BDef4MBZax2R-4H0nE5KzHf4dSo5m-HyfWZmgsed_ADKAxHE</recordid><startdate>20070601</startdate><enddate>20070601</enddate><creator>Mukaiyama, Harunobu</creator><creator>Nishimura, Toshihiro</creator><creator>Shiohara, Hiroaki</creator><creator>Kobayashi, Satoko</creator><creator>Komatsu, Yoshimitsu</creator><creator>Kikuchi, Shinji</creator><creator>Tsuji, Eiichi</creator><creator>Kamada, Noboru</creator><creator>Ohnota, Hideki</creator><creator>Kusama, Hiroshi</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20070601</creationdate><title>Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke</title><author>Mukaiyama, Harunobu ; Nishimura, Toshihiro ; Shiohara, Hiroaki ; Kobayashi, Satoko ; Komatsu, Yoshimitsu ; Kikuchi, Shinji ; Tsuji, Eiichi ; Kamada, Noboru ; Ohnota, Hideki ; Kusama, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c690t-8ace6466dfbc99dcc64069c1dfb318b70275490c1c1305d605349ba09b057a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>acute ischemic stroke</topic><topic>Animals</topic><topic>c-Src kinase</topic><topic>central nervous system penetration</topic><topic>Crystallography, X-Ray</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Models, Molecular</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>pyrazolo[1,5-a]pyrimidine</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spectrophotometry, Infrared</topic><topic>src-Family Kinases - antagonists & inhibitors</topic><topic>Stroke - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mukaiyama, Harunobu</creatorcontrib><creatorcontrib>Nishimura, Toshihiro</creatorcontrib><creatorcontrib>Shiohara, Hiroaki</creatorcontrib><creatorcontrib>Kobayashi, Satoko</creatorcontrib><creatorcontrib>Komatsu, Yoshimitsu</creatorcontrib><creatorcontrib>Kikuchi, Shinji</creatorcontrib><creatorcontrib>Tsuji, Eiichi</creatorcontrib><creatorcontrib>Kamada, Noboru</creatorcontrib><creatorcontrib>Ohnota, Hideki</creatorcontrib><creatorcontrib>Kusama, Hiroshi</creatorcontrib><creatorcontrib>Central Research Laboratory</creatorcontrib><creatorcontrib>Kissei Pharmaceutical Company Ltd</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & Pharmaceutical Bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mukaiyama, Harunobu</au><au>Nishimura, Toshihiro</au><au>Shiohara, Hiroaki</au><au>Kobayashi, Satoko</au><au>Komatsu, Yoshimitsu</au><au>Kikuchi, Shinji</au><au>Tsuji, Eiichi</au><au>Kamada, Noboru</au><au>Ohnota, Hideki</au><au>Kusama, Hiroshi</au><aucorp>Central Research Laboratory</aucorp><aucorp>Kissei Pharmaceutical Company Ltd</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke</atitle><jtitle>Chemical & Pharmaceutical Bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2007-06-01</date><risdate>2007</risdate><volume>55</volume><issue>6</issue><spage>881</spage><epage>889</epage><pages>881-889</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. 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| source | J-STAGE Free; MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | acute ischemic stroke Animals c-Src kinase central nervous system penetration Crystallography, X-Ray Magnetic Resonance Spectroscopy Male Models, Molecular Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - therapeutic use pyrazolo[1,5-a]pyrimidine Pyrimidines - chemistry Pyrimidines - pharmacology Rats Rats, Sprague-Dawley Spectrophotometry, Infrared src-Family Kinases - antagonists & inhibitors Stroke - drug therapy |
| title | Discovery of Novel 2-Anilinopyrazolo[1,5-a]pyrimidine Derivatives as c-Src Kinase Inhibitors for the Treatment of Acute Ischemic Stroke |
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