2-Alkylamino-and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)
This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisost...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2008-12, Vol.18 (23), p.6171-6174 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | WARMUS, Joseph S FLAMME, Cathlin MERRIMAN, Ronald OHREN, Jeffrey PAVLOVSKY, Alexander PRZYBRANOWSKI, Sally TECLE, Haile VALIK, Heather WHITEHEAD, Christopher ERLI ZHANG LU YAN ZHANG BARRETT, Stephen BRIDGES, Alexander HUIFEN CHEN GOWAN, Richard KAUFMAN, Michael SEBOLT-LEOPOLD, Judy LEOPOLD, Wilbur |
| description | This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor. |
| doi_str_mv | 10.1016/j.bmcl.2008.10.015 |
| format | Article |
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An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.</description><identifier>ISSN: 0960-894X</identifier><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3405</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmcl.2008.10.015</identifier><identifier>PMID: 18951019</identifier><language>eng</language><publisher>Amsterdam: Elsevier</publisher><subject>60 APPLIED LIFE SCIENCES ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; BASIC BIOLOGICAL SCIENCES ; Benzamides - chemistry ; Benzamides - pharmacology ; Biological and medical sciences ; Colonic Neoplasms - chemically induced ; Colonic Neoplasms - drug therapy ; Combinatorial Chemistry Techniques ; Drug Screening Assays, Antitumor ; ENZYME INHIBITORS ; ESTERS ; General aspects ; Humans ; Hydroxamic Acids - chemical synthesis ; Hydroxamic Acids - chemistry ; Hydroxamic Acids - pharmacology ; Medical sciences ; Microsomes, Liver - drug effects ; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors ; Molecular Structure ; OXADIAZOLES ; Oxadiazoles - chemical synthesis ; Oxadiazoles - chemistry ; Oxadiazoles - pharmacology ; Pharmacology. 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>2-Alkylamino-and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem Lett</addtitle><description>This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Colonic Neoplasms - chemically induced</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Combinatorial Chemistry Techniques</subject><subject>Drug Screening Assays, Antitumor</subject><subject>ENZYME INHIBITORS</subject><subject>ESTERS</subject><subject>General aspects</subject><subject>Humans</subject><subject>Hydroxamic Acids - chemical synthesis</subject><subject>Hydroxamic Acids - chemistry</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - drug effects</subject><subject>Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors</subject><subject>Molecular Structure</subject><subject>OXADIAZOLES</subject><subject>Oxadiazoles - chemical synthesis</subject><subject>Oxadiazoles - chemistry</subject><subject>Oxadiazoles - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>PHOSPHOTRANSFERASES</subject><subject>SOLUBILITY</subject><subject>STABILITY</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>0968-0896</issn><issn>1464-3405</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkd-K1DAUxoMo7rj6Al5IEBSFzZi0adpeDsv4h91lRRS8K2ly6mQmTWabVLb7Xr6fKR30KuSc3_edk3wIvWR0zSgTH_brtld2nVFapcKasuIRWjEuOMk5LR6jFa0FJVXNf56hZyHsKWWccv4UnbGqLpJFvUJ_MrKxh8nK3jhPpNNY2oO_n0gY2xBNHCNonJGlzS7yC078vdRGPngLgdwuatyCe_C7SQ-p2csIGEKEIeABjlYq6MHF-RKlcTjuAGsIZkjOxu1Ma6LxDs-zA1hQ0fw2ccLyV4JDxDfbK_zuZvMVb79d4YNxMsD75-hJJ22AF6fzHP34uP1--Zlc3376crm5Jiqv6kgKAUWlhNZl13ZKVJBLVdESBC1rVirQRVm2WlJdQaezTELRKc4zkee8oILS_By9Xnx9-osmKBNB7ZR3Lm3ZMEpLlmUJertAx8HfjenhTW-CAmulAz-GhtV5LpgoEpgtoBp8CAN0zXEwvRymZNXMiTb7Zk60mROdaynRJHp1ch_bHvR_ySnCBLw5ATIoabtBOmXCPy6jVSnytOZf9zqs4Q</recordid><startdate>20081201</startdate><enddate>20081201</enddate><creator>WARMUS, Joseph S</creator><creator>FLAMME, Cathlin</creator><creator>MERRIMAN, Ronald</creator><creator>OHREN, Jeffrey</creator><creator>PAVLOVSKY, Alexander</creator><creator>PRZYBRANOWSKI, Sally</creator><creator>TECLE, Haile</creator><creator>VALIK, Heather</creator><creator>WHITEHEAD, Christopher</creator><creator>ERLI ZHANG</creator><creator>LU YAN ZHANG</creator><creator>BARRETT, Stephen</creator><creator>BRIDGES, Alexander</creator><creator>HUIFEN CHEN</creator><creator>GOWAN, Richard</creator><creator>KAUFMAN, Michael</creator><creator>SEBOLT-LEOPOLD, Judy</creator><creator>LEOPOLD, Wilbur</creator><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>OTOTI</scope></search><sort><creationdate>20081201</creationdate><title>2-Alkylamino-and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)</title><author>WARMUS, Joseph S ; FLAMME, Cathlin ; MERRIMAN, Ronald ; OHREN, Jeffrey ; PAVLOVSKY, Alexander ; PRZYBRANOWSKI, Sally ; TECLE, Haile ; VALIK, Heather ; WHITEHEAD, Christopher ; ERLI ZHANG ; LU YAN ZHANG ; BARRETT, Stephen ; BRIDGES, Alexander ; HUIFEN CHEN ; GOWAN, Richard ; KAUFMAN, Michael ; SEBOLT-LEOPOLD, Judy ; LEOPOLD, Wilbur</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-56e58c6dd7fbfc68e3ac807e607917ced577bda0d8efd22ae5fc4426334506003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Benzamides - chemistry</topic><topic>Benzamides - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Colonic Neoplasms - chemically induced</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Combinatorial Chemistry Techniques</topic><topic>Drug Screening Assays, Antitumor</topic><topic>ENZYME INHIBITORS</topic><topic>ESTERS</topic><topic>General aspects</topic><topic>Humans</topic><topic>Hydroxamic Acids - chemical synthesis</topic><topic>Hydroxamic Acids - chemistry</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - drug effects</topic><topic>Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors</topic><topic>Molecular Structure</topic><topic>OXADIAZOLES</topic><topic>Oxadiazoles - chemical synthesis</topic><topic>Oxadiazoles - chemistry</topic><topic>Oxadiazoles - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>PHOSPHOTRANSFERASES</topic><topic>SOLUBILITY</topic><topic>STABILITY</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WARMUS, Joseph S</creatorcontrib><creatorcontrib>FLAMME, Cathlin</creatorcontrib><creatorcontrib>MERRIMAN, Ronald</creatorcontrib><creatorcontrib>OHREN, Jeffrey</creatorcontrib><creatorcontrib>PAVLOVSKY, Alexander</creatorcontrib><creatorcontrib>PRZYBRANOWSKI, Sally</creatorcontrib><creatorcontrib>TECLE, Haile</creatorcontrib><creatorcontrib>VALIK, Heather</creatorcontrib><creatorcontrib>WHITEHEAD, Christopher</creatorcontrib><creatorcontrib>ERLI ZHANG</creatorcontrib><creatorcontrib>LU YAN ZHANG</creatorcontrib><creatorcontrib>BARRETT, Stephen</creatorcontrib><creatorcontrib>BRIDGES, Alexander</creatorcontrib><creatorcontrib>HUIFEN CHEN</creatorcontrib><creatorcontrib>GOWAN, Richard</creatorcontrib><creatorcontrib>KAUFMAN, Michael</creatorcontrib><creatorcontrib>SEBOLT-LEOPOLD, Judy</creatorcontrib><creatorcontrib>LEOPOLD, Wilbur</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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>OSTI.GOV</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>WARMUS, Joseph S</au><au>FLAMME, Cathlin</au><au>MERRIMAN, Ronald</au><au>OHREN, Jeffrey</au><au>PAVLOVSKY, Alexander</au><au>PRZYBRANOWSKI, Sally</au><au>TECLE, Haile</au><au>VALIK, Heather</au><au>WHITEHEAD, Christopher</au><au>ERLI ZHANG</au><au>LU YAN ZHANG</au><au>BARRETT, Stephen</au><au>BRIDGES, Alexander</au><au>HUIFEN CHEN</au><au>GOWAN, Richard</au><au>KAUFMAN, Michael</au><au>SEBOLT-LEOPOLD, Judy</au><au>LEOPOLD, Wilbur</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2-Alkylamino-and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2008-12-01</date><risdate>2008</risdate><volume>18</volume><issue>23</issue><spage>6171</spage><epage>6174</epage><pages>6171-6174</pages><issn>0960-894X</issn><issn>0968-0896</issn><eissn>1464-3405</eissn><eissn>1464-3391</eissn><abstract>This paper reports a second generation MEK inhibitor. The previously reported potent and efficacious MEK inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK inhibitor.</abstract><cop>Amsterdam</cop><pub>Elsevier</pub><pmid>18951019</pmid><doi>10.1016/j.bmcl.2008.10.015</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry, 2008-12, Vol.18 (23), p.6171-6174 |
| issn | 0960-894X 0968-0896 1464-3405 1464-3391 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1007122 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 60 APPLIED LIFE SCIENCES Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology BASIC BIOLOGICAL SCIENCES Benzamides - chemistry Benzamides - pharmacology Biological and medical sciences Colonic Neoplasms - chemically induced Colonic Neoplasms - drug therapy Combinatorial Chemistry Techniques Drug Screening Assays, Antitumor ENZYME INHIBITORS ESTERS General aspects Humans Hydroxamic Acids - chemical synthesis Hydroxamic Acids - chemistry Hydroxamic Acids - pharmacology Medical sciences Microsomes, Liver - drug effects Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Molecular Structure OXADIAZOLES Oxadiazoles - chemical synthesis Oxadiazoles - chemistry Oxadiazoles - pharmacology Pharmacology. Drug treatments PHOSPHOTRANSFERASES SOLUBILITY STABILITY Structure-Activity Relationship |
| title | 2-Alkylamino-and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase) |
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