Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase i...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-04, Vol.54 (7), p.2255-2265 |
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| creator | Goldstein, David M Soth, Michael Gabriel, Tobias Dewdney, Nolan Kuglstatter, Andreas Arzeno, Humberto Chen, Jeffrey Bingenheimer, William Dalrymple, Stacie A Dunn, James Farrell, Robert Frauchiger, Sandra La Fargue, JoAnn Ghate, Manjiri Graves, Bradford Hill, Ronald J Li, Fujun Litman, Renee Loe, Brad McIntosh, Joel McWeeney, Daniel Papp, Eva Park, Jaehyeon Reese, Harlan F Roberts, Richard T Rotstein, David San Pablo, Bong Sarma, Keshab Stahl, Martin Sung, Man-Ling Suttman, Rebecca T Sjogren, Eric B Tan, Yunchou Trejo, Alejandra Welch, Mary Weller, Paul Wong, Brian R Zecic, Hasim |
| description | The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties. |
| doi_str_mv | 10.1021/jm101423y |
| format | Article |
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The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm101423y</identifier><identifier>PMID: 21375264</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Administration, Oral ; Arthritis, Rheumatoid - drug therapy ; Biological Availability ; Cell Line ; Clinical Trials as Topic ; Drug Discovery - methods ; Humans ; Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors ; Mitogen-Activated Protein Kinase 14 - chemistry ; Models, Molecular ; Protein Conformation ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Pyridones - administration & dosage ; Pyridones - chemistry ; Pyridones - pharmacokinetics ; Pyridones - pharmacology ; Pyrimidines - administration & dosage ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Structure-Activity Relationship ; Substrate Specificity</subject><ispartof>Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2255-2265</ispartof><rights>Copyright © 2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm101423y$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm101423y$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21375264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Goldstein, David M</creatorcontrib><creatorcontrib>Soth, Michael</creatorcontrib><creatorcontrib>Gabriel, Tobias</creatorcontrib><creatorcontrib>Dewdney, Nolan</creatorcontrib><creatorcontrib>Kuglstatter, Andreas</creatorcontrib><creatorcontrib>Arzeno, Humberto</creatorcontrib><creatorcontrib>Chen, Jeffrey</creatorcontrib><creatorcontrib>Bingenheimer, William</creatorcontrib><creatorcontrib>Dalrymple, Stacie A</creatorcontrib><creatorcontrib>Dunn, James</creatorcontrib><creatorcontrib>Farrell, Robert</creatorcontrib><creatorcontrib>Frauchiger, Sandra</creatorcontrib><creatorcontrib>La Fargue, JoAnn</creatorcontrib><creatorcontrib>Ghate, Manjiri</creatorcontrib><creatorcontrib>Graves, Bradford</creatorcontrib><creatorcontrib>Hill, Ronald J</creatorcontrib><creatorcontrib>Li, Fujun</creatorcontrib><creatorcontrib>Litman, Renee</creatorcontrib><creatorcontrib>Loe, Brad</creatorcontrib><creatorcontrib>McIntosh, Joel</creatorcontrib><creatorcontrib>McWeeney, Daniel</creatorcontrib><creatorcontrib>Papp, Eva</creatorcontrib><creatorcontrib>Park, Jaehyeon</creatorcontrib><creatorcontrib>Reese, Harlan F</creatorcontrib><creatorcontrib>Roberts, Richard T</creatorcontrib><creatorcontrib>Rotstein, David</creatorcontrib><creatorcontrib>San Pablo, Bong</creatorcontrib><creatorcontrib>Sarma, Keshab</creatorcontrib><creatorcontrib>Stahl, Martin</creatorcontrib><creatorcontrib>Sung, Man-Ling</creatorcontrib><creatorcontrib>Suttman, Rebecca T</creatorcontrib><creatorcontrib>Sjogren, Eric B</creatorcontrib><creatorcontrib>Tan, Yunchou</creatorcontrib><creatorcontrib>Trejo, Alejandra</creatorcontrib><creatorcontrib>Welch, Mary</creatorcontrib><creatorcontrib>Weller, Paul</creatorcontrib><creatorcontrib>Wong, Brian R</creatorcontrib><creatorcontrib>Zecic, Hasim</creatorcontrib><title>Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.</description><subject>Administration, Oral</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Biological Availability</subject><subject>Cell Line</subject><subject>Clinical Trials as Topic</subject><subject>Drug Discovery - methods</subject><subject>Humans</subject><subject>Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 14 - chemistry</subject><subject>Models, Molecular</subject><subject>Protein Conformation</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyridones - administration & dosage</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - pharmacokinetics</subject><subject>Pyridones - pharmacology</subject><subject>Pyrimidines - administration & dosage</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1ks9u1DAQxgMC0aVw4AVQLohdqQP2OJs4x9IWtqKoFdBTVUWT2Nv1yrFDkl01j8WL8Ex4_7S3nkbf6KfvG81MFL3j7BNnyD8va854gmJ4Ho34FBkkkiUvohFjiIApioPoddctGWOCo3gVHSAX2RTTZPTs-tR0lV_rdoj9PE5hjEcJnJq5XfnWNwvt_P0wAYQbAYtBtUEBD9CD0P1isJMmoIOl2jh_CxLqbRfkDJqhNcrf4JEAdbsRtVHGQQbe6Xh8RTU1pvZqEpNTT4Y_GiKMe923tM0G3NqTgwT22ZOn4sZyNtlF_uSJzEJcF1-2ZO0QfzGe1mQslVZvp5iZu0Xo_9JWV71Z6_jcLUxpet92mw01Qv77G_8I-k47ON4g1GsVX7W-18bF342jTr-JXs7Jdvrtvh5G11_Pfp_M4OLy2_nJ8QUQz1gPsiyJSZ4olpKoCHmVi0qkVDKZiDxTrJQZKk1TnWI-lSovxTyXhJnAaYJBHUYfd77hAn9WuuuLOpxTW0tO-1VXyJQjS1mWBvL9nlyVtVZFE5ZD7VA8fEIAPuwAqrpi6VetC4MXnBWbDyseP0z8B2cbwcI</recordid><startdate>20110414</startdate><enddate>20110414</enddate><creator>Goldstein, David M</creator><creator>Soth, Michael</creator><creator>Gabriel, Tobias</creator><creator>Dewdney, Nolan</creator><creator>Kuglstatter, Andreas</creator><creator>Arzeno, Humberto</creator><creator>Chen, Jeffrey</creator><creator>Bingenheimer, William</creator><creator>Dalrymple, Stacie A</creator><creator>Dunn, James</creator><creator>Farrell, Robert</creator><creator>Frauchiger, Sandra</creator><creator>La Fargue, JoAnn</creator><creator>Ghate, Manjiri</creator><creator>Graves, Bradford</creator><creator>Hill, Ronald J</creator><creator>Li, Fujun</creator><creator>Litman, Renee</creator><creator>Loe, Brad</creator><creator>McIntosh, Joel</creator><creator>McWeeney, Daniel</creator><creator>Papp, Eva</creator><creator>Park, Jaehyeon</creator><creator>Reese, Harlan F</creator><creator>Roberts, Richard T</creator><creator>Rotstein, David</creator><creator>San Pablo, Bong</creator><creator>Sarma, Keshab</creator><creator>Stahl, Martin</creator><creator>Sung, Man-Ling</creator><creator>Suttman, Rebecca T</creator><creator>Sjogren, Eric B</creator><creator>Tan, Yunchou</creator><creator>Trejo, Alejandra</creator><creator>Welch, Mary</creator><creator>Weller, Paul</creator><creator>Wong, Brian R</creator><creator>Zecic, Hasim</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20110414</creationdate><title>Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase</title><author>Goldstein, David M ; Soth, Michael ; Gabriel, Tobias ; Dewdney, Nolan ; Kuglstatter, Andreas ; Arzeno, Humberto ; Chen, Jeffrey ; Bingenheimer, William ; Dalrymple, Stacie A ; Dunn, James ; Farrell, Robert ; Frauchiger, Sandra ; La Fargue, JoAnn ; Ghate, Manjiri ; Graves, Bradford ; Hill, Ronald J ; Li, Fujun ; Litman, Renee ; Loe, Brad ; McIntosh, Joel ; McWeeney, Daniel ; Papp, Eva ; Park, Jaehyeon ; Reese, Harlan F ; Roberts, Richard T ; Rotstein, David ; San Pablo, Bong ; Sarma, Keshab ; Stahl, Martin ; Sung, Man-Ling ; Suttman, Rebecca T ; Sjogren, Eric B ; Tan, Yunchou ; Trejo, Alejandra ; Welch, Mary ; Weller, Paul ; Wong, Brian R ; Zecic, Hasim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a170t-8bba0814d06a3ca21c93c36ab084397d0b872dea5e62958d9b3f98a27325429b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Administration, Oral</topic><topic>Arthritis, Rheumatoid - 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Med. Chem</addtitle><date>2011-04-14</date><risdate>2011</risdate><volume>54</volume><issue>7</issue><spage>2255</spage><epage>2265</epage><pages>2255-2265</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21375264</pmid><doi>10.1021/jm101423y</doi><tpages>11</tpages></addata></record> |
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| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2255-2265 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Administration, Oral Arthritis, Rheumatoid - drug therapy Biological Availability Cell Line Clinical Trials as Topic Drug Discovery - methods Humans Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors Mitogen-Activated Protein Kinase 14 - chemistry Models, Molecular Protein Conformation Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Pyridones - administration & dosage Pyridones - chemistry Pyridones - pharmacokinetics Pyridones - pharmacology Pyrimidines - administration & dosage Pyrimidines - chemistry Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Structure-Activity Relationship Substrate Specificity |
| title | Discovery of 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (Pamapimod) and 6-(2,4-Difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as Orally Bioavailable and Highly Selective Inhibitors of p38α Mitogen-Activated Protein Kinase |
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