Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative c...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-04, Vol.19 (8), p.2244-2248 |
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| creator | Seefeld, Mark A. Rouse, Meagan B. McNulty, Kenneth C. Sun, Lihui Wang, Jizhou Yamashita, Dennis S. Luengo, Juan I. Zhang, ShuYun Minthorn, Elisabeth A. Concha, Nestor O. Heerding, Dirk A. |
| description | A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.
A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β. |
| doi_str_mv | 10.1016/j.bmcl.2009.02.094 |
| format | Article |
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7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.
A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.02.094</identifier><identifier>PMID: 19285393</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>AKT ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Crystallography, X-Ray ; Drug Discovery - methods ; General aspects ; Humans ; Kinase ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Pyridines - chemical synthesis ; Pyridines - pharmacology ; Thienopyridines ; Thiophenes - chemical synthesis ; Thiophenes - chemistry ; Thiophenes - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-04, Vol.19 (8), p.2244-2248</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-daad0e8ba84c40414d7b6def13c4f50a4ea184f5c98b8d7aa454dc375ce822183</citedby><cites>FETCH-LOGICAL-c415t-daad0e8ba84c40414d7b6def13c4f50a4ea184f5c98b8d7aa454dc375ce822183</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09002492$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21391793$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19285393$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seefeld, Mark A.</creatorcontrib><creatorcontrib>Rouse, Meagan B.</creatorcontrib><creatorcontrib>McNulty, Kenneth C.</creatorcontrib><creatorcontrib>Sun, Lihui</creatorcontrib><creatorcontrib>Wang, Jizhou</creatorcontrib><creatorcontrib>Yamashita, Dennis S.</creatorcontrib><creatorcontrib>Luengo, Juan I.</creatorcontrib><creatorcontrib>Zhang, ShuYun</creatorcontrib><creatorcontrib>Minthorn, Elisabeth A.</creatorcontrib><creatorcontrib>Concha, Nestor O.</creatorcontrib><creatorcontrib>Heerding, Dirk A.</creatorcontrib><title>Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.
A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.</description><subject>AKT</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Drug Discovery - methods</subject><subject>General aspects</subject><subject>Humans</subject><subject>Kinase</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacology</subject><subject>Thienopyridines</subject><subject>Thiophenes - chemical synthesis</subject><subject>Thiophenes - chemistry</subject><subject>Thiophenes - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1v1DAQhi0EokvhD3BAudBb0hnHSRyJS9UPQK3Epai9WY490XpJ4mBnK_bf18uu4AanmcPzzsfD2HuEAgHr803RjWYoOEBbAC-gFS_YCkUt8lJA9ZKtoK0hl614PGFvYtwAoAAhXrMTbLmsyrZcsYcrF41_orDLfJ9V-bwLwQ8-FWfdtBtyni9r5-c1TWR06PwvPTpLMdMxm_1C05Jd3N5nP9ykI2VuWrvOLT7Et-xVr4dI7471lH2_ub6__JLfffv89fLiLjcCqyW3Wlsg2WkpTLoNhW262lKPpRF9BVqQRpk608pO2kZrUQlryqYyJDlHWZ6ys8PcOfifW4qLGtNDNAx6Ir-Nqm4QkWP9X5BDVXLgmEB-AE3wMQbq1RzcqMNOIai9d7VRe-9q710BV8l7Cn04Tt92I9m_kaPoBHw8AjoaPfRBT8bFP1za22Lzm_t04ChJe3IUVDSOJkPWBTKLst79645n4tyiIg</recordid><startdate>20090415</startdate><enddate>20090415</enddate><creator>Seefeld, Mark A.</creator><creator>Rouse, Meagan B.</creator><creator>McNulty, Kenneth C.</creator><creator>Sun, Lihui</creator><creator>Wang, Jizhou</creator><creator>Yamashita, Dennis S.</creator><creator>Luengo, Juan I.</creator><creator>Zhang, ShuYun</creator><creator>Minthorn, Elisabeth A.</creator><creator>Concha, Nestor O.</creator><creator>Heerding, Dirk A.</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>20090415</creationdate><title>Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors</title><author>Seefeld, Mark A. ; Rouse, Meagan B. ; McNulty, Kenneth C. ; Sun, Lihui ; Wang, Jizhou ; Yamashita, Dennis S. ; Luengo, Juan I. ; Zhang, ShuYun ; Minthorn, Elisabeth A. ; Concha, Nestor O. ; Heerding, Dirk A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-daad0e8ba84c40414d7b6def13c4f50a4ea184f5c98b8d7aa454dc375ce822183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>AKT</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Drug Discovery - methods</topic><topic>General aspects</topic><topic>Humans</topic><topic>Kinase</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacology</topic><topic>Thienopyridines</topic><topic>Thiophenes - chemical synthesis</topic><topic>Thiophenes - chemistry</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seefeld, Mark A.</creatorcontrib><creatorcontrib>Rouse, Meagan B.</creatorcontrib><creatorcontrib>McNulty, Kenneth C.</creatorcontrib><creatorcontrib>Sun, Lihui</creatorcontrib><creatorcontrib>Wang, Jizhou</creatorcontrib><creatorcontrib>Yamashita, Dennis S.</creatorcontrib><creatorcontrib>Luengo, Juan I.</creatorcontrib><creatorcontrib>Zhang, ShuYun</creatorcontrib><creatorcontrib>Minthorn, Elisabeth A.</creatorcontrib><creatorcontrib>Concha, Nestor O.</creatorcontrib><creatorcontrib>Heerding, Dirk A.</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>Seefeld, Mark A.</au><au>Rouse, Meagan B.</au><au>McNulty, Kenneth C.</au><au>Sun, Lihui</au><au>Wang, Jizhou</au><au>Yamashita, Dennis S.</au><au>Luengo, Juan I.</au><au>Zhang, ShuYun</au><au>Minthorn, Elisabeth A.</au><au>Concha, Nestor O.</au><au>Heerding, Dirk A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-04-15</date><risdate>2009</risdate><volume>19</volume><issue>8</issue><spage>2244</spage><epage>2248</epage><pages>2244-2248</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.
A pyrrolopyridinyl thiophene carboxamide
7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of
7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3β.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19285393</pmid><doi>10.1016/j.bmcl.2009.02.094</doi><tpages>5</tpages></addata></record> |
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| subjects | AKT Animals Antineoplastic agents Biological and medical sciences Crystallography, X-Ray Drug Discovery - methods General aspects Humans Kinase Medical sciences Mice Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Pyridines - chemical synthesis Pyridines - pharmacology Thienopyridines Thiophenes - chemical synthesis Thiophenes - chemistry Thiophenes - pharmacology |
| title | Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors |
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