2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization
We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC 50 values as low as 19 nM and moderate selectivity against a kinase panel. Com...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010, Vol.20 (1), p.334-337 |
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| creator | Harris, Christopher M. Ericsson, Anna M. Argiriadi, Maria A. Barberis, Claude Borhani, David W. Burchat, Andrew Calderwood, David J. Cunha, George A. Dixon, Richard W. Frank, Kristine E. Johnson, Eric F. Kamens, Joanne Kwak, Silvia Li, Biqin Mullen, Kelly D. Perron, Denise C. Wang, Lu Wishart, Neil Wu, Xiaoyun Zhang, Xiaolei Zmetra, Tami R. Talanian, Robert V. |
| description | We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC
50 values as low as 19
nM and moderate selectivity against a kinase panel. Compounds
15,
31a, and
31b inhibit TNFα production in peripheral human monocytes. |
| doi_str_mv | 10.1016/j.bmcl.2009.10.103 |
| format | Article |
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50 values as low as 19
nM and moderate selectivity against a kinase panel. Compounds
15,
31a, and
31b inhibit TNFα production in peripheral human monocytes.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.10.103</identifier><identifier>PMID: 19926477</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - pharmacokinetics ; Binding Sites ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Computer Simulation ; Crystallography, X-Ray ; Diaminopyrimidine ; Humans ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins - metabolism ; MAPKAP-K2 ; Medical sciences ; MK2 ; Pharmacology. Drug treatments ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacokinetics ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - metabolism ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; TNFα ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010, Vol.20 (1), p.334-337</ispartof><rights>2009 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2009 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-6dbc05222efb6920441b77466a243ccc804ae732e6648f33a40cabf20a71160b3</citedby><cites>FETCH-LOGICAL-c416t-6dbc05222efb6920441b77466a243ccc804ae732e6648f33a40cabf20a71160b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09015145$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22314253$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19926477$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Harris, Christopher M.</creatorcontrib><creatorcontrib>Ericsson, Anna M.</creatorcontrib><creatorcontrib>Argiriadi, Maria A.</creatorcontrib><creatorcontrib>Barberis, Claude</creatorcontrib><creatorcontrib>Borhani, David W.</creatorcontrib><creatorcontrib>Burchat, Andrew</creatorcontrib><creatorcontrib>Calderwood, David J.</creatorcontrib><creatorcontrib>Cunha, George A.</creatorcontrib><creatorcontrib>Dixon, Richard W.</creatorcontrib><creatorcontrib>Frank, Kristine E.</creatorcontrib><creatorcontrib>Johnson, Eric F.</creatorcontrib><creatorcontrib>Kamens, Joanne</creatorcontrib><creatorcontrib>Kwak, Silvia</creatorcontrib><creatorcontrib>Li, Biqin</creatorcontrib><creatorcontrib>Mullen, Kelly D.</creatorcontrib><creatorcontrib>Perron, Denise C.</creatorcontrib><creatorcontrib>Wang, Lu</creatorcontrib><creatorcontrib>Wishart, Neil</creatorcontrib><creatorcontrib>Wu, Xiaoyun</creatorcontrib><creatorcontrib>Zhang, Xiaolei</creatorcontrib><creatorcontrib>Zmetra, Tami R.</creatorcontrib><creatorcontrib>Talanian, Robert V.</creatorcontrib><title>2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC
50 values as low as 19
nM and moderate selectivity against a kinase panel. Compounds
15,
31a, and
31b inhibit TNFα production in peripheral human monocytes.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - pharmacokinetics</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Diaminopyrimidine</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>MAPKAP-K2</subject><subject>Medical sciences</subject><subject>MK2</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Structure-Activity Relationship</subject><subject>TNFα</subject><subject>Tumor Necrosis Factor-alpha - metabolism</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>eNp9kEtv1DAUha2Kig6FP8ACZQNsmmBf3zgTxAb1xahFINFK7CzbuREe5THYDlL59c10Ru2uqysdfefo6mPsreCF4EJ9Whe2d10BnNfFQyYP2EKgwlwiL1-wBa8Vz5c1_j5ir2Jccy6QI75kR6KuQWFVLdgtnGB-5k3vh3FzF3zvGz9Q9v0KMj_88danMcQi-2lCylarz9mvFCaXpkC5NZGaJygbN2lu_zfJj8NrdtiaLtKb_T1mtxfnN6ff8usfl6vTr9e5Q6FSrhrreAkA1FpVw_ybsFWFShlA6ZxbcjRUSSClcNlKaZA7Y1vgphJCcSuP2cfd7iaMfyeKSfc-Ouo6M9A4RV1JWZdclmomPzxLggCJpapnEHagC2OMgVq9ma2YcKcF11vteq232vVW-y6Tc-ndfn2yPTVPlb3nGXi_B0x0pmuDGZyPjxyAFAjldujLjqPZ2j9PQUfnaXDU-EAu6Wb0z_1xDz6ynyI</recordid><startdate>2010</startdate><enddate>2010</enddate><creator>Harris, Christopher M.</creator><creator>Ericsson, Anna M.</creator><creator>Argiriadi, Maria A.</creator><creator>Barberis, Claude</creator><creator>Borhani, David W.</creator><creator>Burchat, Andrew</creator><creator>Calderwood, David J.</creator><creator>Cunha, George A.</creator><creator>Dixon, Richard W.</creator><creator>Frank, Kristine E.</creator><creator>Johnson, Eric F.</creator><creator>Kamens, Joanne</creator><creator>Kwak, Silvia</creator><creator>Li, Biqin</creator><creator>Mullen, Kelly D.</creator><creator>Perron, Denise C.</creator><creator>Wang, Lu</creator><creator>Wishart, Neil</creator><creator>Wu, Xiaoyun</creator><creator>Zhang, Xiaolei</creator><creator>Zmetra, Tami R.</creator><creator>Talanian, Robert V.</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>2010</creationdate><title>2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization</title><author>Harris, Christopher M. ; Ericsson, Anna M. ; Argiriadi, Maria A. ; Barberis, Claude ; Borhani, David W. ; Burchat, Andrew ; Calderwood, David J. ; Cunha, George A. ; Dixon, Richard W. ; Frank, Kristine E. ; Johnson, Eric F. ; Kamens, Joanne ; Kwak, Silvia ; Li, Biqin ; Mullen, Kelly D. ; Perron, Denise C. ; Wang, Lu ; Wishart, Neil ; Wu, Xiaoyun ; Zhang, Xiaolei ; Zmetra, Tami R. ; Talanian, Robert V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-6dbc05222efb6920441b77466a243ccc804ae732e6648f33a40cabf20a71160b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - chemistry</topic><topic>Anti-Inflammatory Agents - pharmacokinetics</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray</topic><topic>Diaminopyrimidine</topic><topic>Humans</topic><topic>Intracellular Signaling Peptides and Proteins - antagonists & inhibitors</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>MAPKAP-K2</topic><topic>Medical sciences</topic><topic>MK2</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Structure-Activity Relationship</topic><topic>TNFα</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Harris, Christopher M.</creatorcontrib><creatorcontrib>Ericsson, Anna M.</creatorcontrib><creatorcontrib>Argiriadi, Maria A.</creatorcontrib><creatorcontrib>Barberis, Claude</creatorcontrib><creatorcontrib>Borhani, David W.</creatorcontrib><creatorcontrib>Burchat, Andrew</creatorcontrib><creatorcontrib>Calderwood, David J.</creatorcontrib><creatorcontrib>Cunha, George A.</creatorcontrib><creatorcontrib>Dixon, Richard W.</creatorcontrib><creatorcontrib>Frank, Kristine E.</creatorcontrib><creatorcontrib>Johnson, Eric F.</creatorcontrib><creatorcontrib>Kamens, Joanne</creatorcontrib><creatorcontrib>Kwak, Silvia</creatorcontrib><creatorcontrib>Li, Biqin</creatorcontrib><creatorcontrib>Mullen, Kelly D.</creatorcontrib><creatorcontrib>Perron, Denise C.</creatorcontrib><creatorcontrib>Wang, Lu</creatorcontrib><creatorcontrib>Wishart, Neil</creatorcontrib><creatorcontrib>Wu, Xiaoyun</creatorcontrib><creatorcontrib>Zhang, Xiaolei</creatorcontrib><creatorcontrib>Zmetra, Tami R.</creatorcontrib><creatorcontrib>Talanian, Robert V.</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Harris, Christopher M.</au><au>Ericsson, Anna M.</au><au>Argiriadi, Maria A.</au><au>Barberis, Claude</au><au>Borhani, David W.</au><au>Burchat, Andrew</au><au>Calderwood, David J.</au><au>Cunha, George A.</au><au>Dixon, Richard W.</au><au>Frank, Kristine E.</au><au>Johnson, Eric F.</au><au>Kamens, Joanne</au><au>Kwak, Silvia</au><au>Li, Biqin</au><au>Mullen, Kelly D.</au><au>Perron, Denise C.</au><au>Wang, Lu</au><au>Wishart, Neil</au><au>Wu, Xiaoyun</au><au>Zhang, Xiaolei</au><au>Zmetra, Tami R.</au><au>Talanian, Robert V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010</date><risdate>2010</risdate><volume>20</volume><issue>1</issue><spage>334</spage><epage>337</epage><pages>334-337</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC
50 values as low as 19
nM and moderate selectivity against a kinase panel. Compounds
15,
31a, and
31b inhibit TNFα production in peripheral human monocytes.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19926477</pmid><doi>10.1016/j.bmcl.2009.10.103</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010, Vol.20 (1), p.334-337 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Animals Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacokinetics Binding Sites Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Computer Simulation Crystallography, X-Ray Diaminopyrimidine Humans Intracellular Signaling Peptides and Proteins - antagonists & inhibitors Intracellular Signaling Peptides and Proteins - metabolism MAPKAP-K2 Medical sciences MK2 Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacokinetics Rats Rats, Sprague-Dawley Structure-Activity Relationship TNFα Tumor Necrosis Factor-alpha - metabolism |
| title | 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization |
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