5-Amino-pyrazoles as potent and selective p38α inhibitors
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibiti...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-12, Vol.20 (23), p.6886-6889 |
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| creator | Das, Jagabandhu Moquin, Robert V. Dyckman, Alaric J. Li, Tianle Pitt, Sidney Zhang, Rosemary Shen, Ding Ren McIntyre, Kim W. Gillooly, Kathleen Doweyko, Arthur M. Newitt, John A. Sack, John S. Zhang, Hongjian Kiefer, Susan E. Kish, Kevin McKinnon, Murray Barrish, Joel C. Dodd, John H. Schieven, Gary L. Leftheris, Katerina |
| description | The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed. |
| doi_str_mv | 10.1016/j.bmcl.2010.10.034 |
| format | Article |
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2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.10.034</identifier><identifier>PMID: 21035336</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Amino-pyrazoles ; Animals ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Crystallography, X-Ray ; Medical sciences ; Mice ; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors ; Mitogen-Activated Protein Kinase 14 - chemistry ; p38 Inhibitors ; Pharmacology. Drug treatments ; Protein Binding ; Protein Conformation ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Structure-Activity Relationship ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; Tumor Necrosis Factor-alpha - biosynthesis</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-12, Vol.20 (23), p.6886-6889</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-5cd7149036bb60a0c54717620c6ac617d1c4457b073520154f135c82d2a28093</citedby><cites>FETCH-LOGICAL-c385t-5cd7149036bb60a0c54717620c6ac617d1c4457b073520154f135c82d2a28093</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.2010.10.034$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23428449$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21035336$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Das, Jagabandhu</creatorcontrib><creatorcontrib>Moquin, Robert V.</creatorcontrib><creatorcontrib>Dyckman, Alaric J.</creatorcontrib><creatorcontrib>Li, Tianle</creatorcontrib><creatorcontrib>Pitt, Sidney</creatorcontrib><creatorcontrib>Zhang, Rosemary</creatorcontrib><creatorcontrib>Shen, Ding Ren</creatorcontrib><creatorcontrib>McIntyre, Kim W.</creatorcontrib><creatorcontrib>Gillooly, Kathleen</creatorcontrib><creatorcontrib>Doweyko, Arthur M.</creatorcontrib><creatorcontrib>Newitt, John A.</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Zhang, Hongjian</creatorcontrib><creatorcontrib>Kiefer, Susan E.</creatorcontrib><creatorcontrib>Kish, Kevin</creatorcontrib><creatorcontrib>McKinnon, Murray</creatorcontrib><creatorcontrib>Barrish, Joel C.</creatorcontrib><creatorcontrib>Dodd, John H.</creatorcontrib><creatorcontrib>Schieven, Gary L.</creatorcontrib><creatorcontrib>Leftheris, Katerina</creatorcontrib><title>5-Amino-pyrazoles as potent and selective p38α inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.</description><subject>Amino-pyrazoles</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Crystallography, X-Ray</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 14 - chemistry</subject><subject>p38 Inhibitors</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Necrosis Factor-alpha - antagonists & inhibitors</subject><subject>Tumor Necrosis Factor-alpha - biosynthesis</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>eNp9kMtKAzEUhoMotlZfwIXMRlxNPUlOMlNxU4o3KLjpwl3IZFJMmZvJtFDfyhfxmZyxVXeuDvx85_Cfj5BzCmMKVF6vxllpijGD72AMHA_IkKLEmCOIQzKEiYQ4neDLgJyEsAKgCIjHZMAocMG5HJIbEU9LV9Vxs_X6vS5siHSImrq1VRvpKo-CLaxp3cZGDU8_PyJXvbrMtbUPp-RoqYtgz_ZzRBb3d4vZYzx_fniaTeex4aloY2HyhOIEuMwyCRqMwIQmkoGR2kia5NQgiiSDhIvuFYFLyoVJWc40S2HCR-Rqd7bx9dvahlaVLhhbFLqy9TqoRHKaIEPoSLYjja9D8HapGu9K7beKguqNqZXqjaneWJ91xrqli_35dVba_HflR1EHXO4BHYwull5XxoU_jiNLEfuetzvOdi42znoVjLOVsbnznUGV1-6_Hl-xiIdD</recordid><startdate>20101201</startdate><enddate>20101201</enddate><creator>Das, Jagabandhu</creator><creator>Moquin, Robert V.</creator><creator>Dyckman, Alaric J.</creator><creator>Li, Tianle</creator><creator>Pitt, Sidney</creator><creator>Zhang, Rosemary</creator><creator>Shen, Ding Ren</creator><creator>McIntyre, Kim W.</creator><creator>Gillooly, Kathleen</creator><creator>Doweyko, Arthur M.</creator><creator>Newitt, John A.</creator><creator>Sack, John S.</creator><creator>Zhang, Hongjian</creator><creator>Kiefer, Susan E.</creator><creator>Kish, Kevin</creator><creator>McKinnon, Murray</creator><creator>Barrish, Joel C.</creator><creator>Dodd, John H.</creator><creator>Schieven, Gary L.</creator><creator>Leftheris, Katerina</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>7X8</scope></search><sort><creationdate>20101201</creationdate><title>5-Amino-pyrazoles as potent and selective p38α inhibitors</title><author>Das, Jagabandhu ; Moquin, Robert V. ; Dyckman, Alaric J. ; Li, Tianle ; Pitt, Sidney ; Zhang, Rosemary ; Shen, Ding Ren ; McIntyre, Kim W. ; Gillooly, Kathleen ; Doweyko, Arthur M. ; Newitt, John A. ; Sack, John S. ; Zhang, Hongjian ; Kiefer, Susan E. ; Kish, Kevin ; McKinnon, Murray ; Barrish, Joel C. ; Dodd, John H. ; Schieven, Gary L. ; Leftheris, Katerina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-5cd7149036bb60a0c54717620c6ac617d1c4457b073520154f135c82d2a28093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino-pyrazoles</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Crystallography, X-Ray</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinase 14 - chemistry</topic><topic>p38 Inhibitors</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Necrosis Factor-alpha - antagonists & inhibitors</topic><topic>Tumor Necrosis Factor-alpha - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Das, Jagabandhu</creatorcontrib><creatorcontrib>Moquin, Robert V.</creatorcontrib><creatorcontrib>Dyckman, Alaric J.</creatorcontrib><creatorcontrib>Li, Tianle</creatorcontrib><creatorcontrib>Pitt, Sidney</creatorcontrib><creatorcontrib>Zhang, Rosemary</creatorcontrib><creatorcontrib>Shen, Ding Ren</creatorcontrib><creatorcontrib>McIntyre, Kim W.</creatorcontrib><creatorcontrib>Gillooly, Kathleen</creatorcontrib><creatorcontrib>Doweyko, Arthur M.</creatorcontrib><creatorcontrib>Newitt, John A.</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Zhang, Hongjian</creatorcontrib><creatorcontrib>Kiefer, Susan E.</creatorcontrib><creatorcontrib>Kish, Kevin</creatorcontrib><creatorcontrib>McKinnon, Murray</creatorcontrib><creatorcontrib>Barrish, Joel C.</creatorcontrib><creatorcontrib>Dodd, John H.</creatorcontrib><creatorcontrib>Schieven, Gary L.</creatorcontrib><creatorcontrib>Leftheris, Katerina</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>Das, Jagabandhu</au><au>Moquin, Robert V.</au><au>Dyckman, Alaric J.</au><au>Li, Tianle</au><au>Pitt, Sidney</au><au>Zhang, Rosemary</au><au>Shen, Ding Ren</au><au>McIntyre, Kim W.</au><au>Gillooly, Kathleen</au><au>Doweyko, Arthur M.</au><au>Newitt, John A.</au><au>Sack, John S.</au><au>Zhang, Hongjian</au><au>Kiefer, Susan E.</au><au>Kish, Kevin</au><au>McKinnon, Murray</au><au>Barrish, Joel C.</au><au>Dodd, John H.</au><au>Schieven, Gary L.</au><au>Leftheris, Katerina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-Amino-pyrazoles as potent and selective p38α inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-12-01</date><risdate>2010</risdate><volume>20</volume><issue>23</issue><spage>6886</spage><epage>6889</epage><pages>6886-6889</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNF production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.
The synthesis and structure–activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound
2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound
2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog
2f bound to unphosphorylated p38α is also disclosed.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21035336</pmid><doi>10.1016/j.bmcl.2010.10.034</doi><tpages>4</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2010-12, Vol.20 (23), p.6886-6889 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Amino-pyrazoles Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Crystallography, X-Ray Medical sciences Mice Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors Mitogen-Activated Protein Kinase 14 - chemistry p38 Inhibitors Pharmacology. Drug treatments Protein Binding Protein Conformation Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - biosynthesis |
| title | 5-Amino-pyrazoles as potent and selective p38α inhibitors |
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