Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-12, Vol.51 (23), p.7478-7485 |
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| container_title | Journal of medicinal chemistry |
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| creator | Chen, Chen Wu, Dongpei Guo, Zhiqiang Xie, Qiu Reinhart, Greg J Madan, Ajay Wen, Jenny Chen, Takung Huang, Charles Q Chen, Mi Chen, Yongsheng Tucci, Fabio C Rowbottom, Martin Pontillo, Joseph Zhu, Yun-Fei Wade, Warren Saunders, John Bozigian, Haig Struthers, R. Scott |
| description | The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis. |
| doi_str_mv | 10.1021/jm8006454 |
| format | Article |
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Scott</creator><creatorcontrib>Chen, Chen ; Wu, Dongpei ; Guo, Zhiqiang ; Xie, Qiu ; Reinhart, Greg J ; Madan, Ajay ; Wen, Jenny ; Chen, Takung ; Huang, Charles Q ; Chen, Mi ; Chen, Yongsheng ; Tucci, Fabio C ; Rowbottom, Martin ; Pontillo, Joseph ; Zhu, Yun-Fei ; Wade, Warren ; Saunders, John ; Bozigian, Haig ; Struthers, R. Scott</creatorcontrib><description>The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm8006454</identifier><identifier>PMID: 19006286</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Caco-2 Cells ; Cytochrome P-450 CYP3A Inhibitors ; Drug Discovery ; Drug Evaluation, Preclinical ; Hormones. Endocrine system ; Humans ; Hydrocarbons, Fluorinated - chemistry ; Hydrocarbons, Fluorinated - metabolism ; Hydrocarbons, Fluorinated - pharmacology ; Macaca fascicularis ; Male ; Medical sciences ; Microsomes, Liver - chemistry ; Microsomes, Liver - metabolism ; Molecular Structure ; Pharmacology. Drug treatments ; Pyrimidines - chemistry ; Pyrimidines - metabolism ; Pyrimidines - pharmacology ; Receptors, LHRH - antagonists & inhibitors ; Stereoisomerism ; Structure-Activity Relationship ; Time Factors</subject><ispartof>Journal of medicinal chemistry, 2008-12, Vol.51 (23), p.7478-7485</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-ac432e59c54d7afd1cd60c667f47468f5233ede70de0c295c61eb2f014c860773</citedby><cites>FETCH-LOGICAL-a381t-ac432e59c54d7afd1cd60c667f47468f5233ede70de0c295c61eb2f014c860773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm8006454$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm8006454$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20965719$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19006286$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chen</creatorcontrib><creatorcontrib>Wu, Dongpei</creatorcontrib><creatorcontrib>Guo, Zhiqiang</creatorcontrib><creatorcontrib>Xie, Qiu</creatorcontrib><creatorcontrib>Reinhart, Greg J</creatorcontrib><creatorcontrib>Madan, Ajay</creatorcontrib><creatorcontrib>Wen, Jenny</creatorcontrib><creatorcontrib>Chen, Takung</creatorcontrib><creatorcontrib>Huang, Charles Q</creatorcontrib><creatorcontrib>Chen, Mi</creatorcontrib><creatorcontrib>Chen, Yongsheng</creatorcontrib><creatorcontrib>Tucci, Fabio C</creatorcontrib><creatorcontrib>Rowbottom, Martin</creatorcontrib><creatorcontrib>Pontillo, Joseph</creatorcontrib><creatorcontrib>Zhu, Yun-Fei</creatorcontrib><creatorcontrib>Wade, Warren</creatorcontrib><creatorcontrib>Saunders, John</creatorcontrib><creatorcontrib>Bozigian, Haig</creatorcontrib><creatorcontrib>Struthers, R. Scott</creatorcontrib><title>Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Caco-2 Cells</subject><subject>Cytochrome P-450 CYP3A Inhibitors</subject><subject>Drug Discovery</subject><subject>Drug Evaluation, Preclinical</subject><subject>Hormones. Endocrine system</subject><subject>Humans</subject><subject>Hydrocarbons, Fluorinated - chemistry</subject><subject>Hydrocarbons, Fluorinated - metabolism</subject><subject>Hydrocarbons, Fluorinated - pharmacology</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - chemistry</subject><subject>Microsomes, Liver - metabolism</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptors, LHRH - antagonists & inhibitors</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Time Factors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkk1v1DAQhgMC0VI48AeQL1RdUYPtJM7mWJW2Cypt1RYJqUKR15l0vTh2sJ1qA-K_421W7YWLv-Z537HHkyRvKPlACaMfl-2UEJ7l2dNkm-aM4GxKsmfJNiGMYcZZupW89H5JCEkpS18kW7SMPJvy7Se7n5SX9g7cgGyDrmyt-hZd4r33E5zhPwzf5HiP4WPdW2dxilsIC7saugWYQU_iQQw2Y5Djm-DUuFljg_4xB_N7jWV4PMBsn-Na2VW0ul8thjoq2Qx3g1OtqpXBFEdhHMcU9zLRKmP_zvswOBEA7R1pcWu1Wk32kUAXNoAJSJganTuh9YAO7oTSYq4BnVnTQRdUDejAhCgyyof1O8MC0KxvhUEn1ojaBme7mPsSNAivzC2aWddaA-gSZDSw7lXyvBHaw-vNvJN8Oz66Ppzh0_OTz4cHp1ikUxqwkFnKIC9lntWFaGoqa04k50WTFRmfNjlLU6ihIDUQycpccgpz1hCaySknRZHuJLujb-fsrx58qNr4P6C1MGB7X3HOS5oXZQQnIyid9d5BU3WxgsINFSXVuimqh6aI7NuNaT9voX4kN10QgXcbQHgpdOOEkco_cIyUPC_oOikeuVhGWD3EhftZ8SIt8ur64qr6npbHZ18vvlSzR18hfbW0vTOxdv-54D9rOdv-</recordid><startdate>20081211</startdate><enddate>20081211</enddate><creator>Chen, Chen</creator><creator>Wu, Dongpei</creator><creator>Guo, Zhiqiang</creator><creator>Xie, Qiu</creator><creator>Reinhart, Greg J</creator><creator>Madan, Ajay</creator><creator>Wen, Jenny</creator><creator>Chen, Takung</creator><creator>Huang, Charles Q</creator><creator>Chen, Mi</creator><creator>Chen, Yongsheng</creator><creator>Tucci, Fabio C</creator><creator>Rowbottom, Martin</creator><creator>Pontillo, Joseph</creator><creator>Zhu, Yun-Fei</creator><creator>Wade, Warren</creator><creator>Saunders, John</creator><creator>Bozigian, Haig</creator><creator>Struthers, R. Scott</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>20081211</creationdate><title>Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor</title><author>Chen, Chen ; Wu, Dongpei ; Guo, Zhiqiang ; Xie, Qiu ; Reinhart, Greg J ; Madan, Ajay ; Wen, Jenny ; Chen, Takung ; Huang, Charles Q ; Chen, Mi ; Chen, Yongsheng ; Tucci, Fabio C ; Rowbottom, Martin ; Pontillo, Joseph ; Zhu, Yun-Fei ; Wade, Warren ; Saunders, John ; Bozigian, Haig ; Struthers, R. Scott</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-ac432e59c54d7afd1cd60c667f47468f5233ede70de0c295c61eb2f014c860773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Caco-2 Cells</topic><topic>Cytochrome P-450 CYP3A Inhibitors</topic><topic>Drug Discovery</topic><topic>Drug Evaluation, Preclinical</topic><topic>Hormones. Endocrine system</topic><topic>Humans</topic><topic>Hydrocarbons, Fluorinated - chemistry</topic><topic>Hydrocarbons, Fluorinated - metabolism</topic><topic>Hydrocarbons, Fluorinated - pharmacology</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - chemistry</topic><topic>Microsomes, Liver - metabolism</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptors, LHRH - antagonists & inhibitors</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chen</creatorcontrib><creatorcontrib>Wu, Dongpei</creatorcontrib><creatorcontrib>Guo, Zhiqiang</creatorcontrib><creatorcontrib>Xie, Qiu</creatorcontrib><creatorcontrib>Reinhart, Greg J</creatorcontrib><creatorcontrib>Madan, Ajay</creatorcontrib><creatorcontrib>Wen, Jenny</creatorcontrib><creatorcontrib>Chen, Takung</creatorcontrib><creatorcontrib>Huang, Charles Q</creatorcontrib><creatorcontrib>Chen, Mi</creatorcontrib><creatorcontrib>Chen, Yongsheng</creatorcontrib><creatorcontrib>Tucci, Fabio C</creatorcontrib><creatorcontrib>Rowbottom, Martin</creatorcontrib><creatorcontrib>Pontillo, Joseph</creatorcontrib><creatorcontrib>Zhu, Yun-Fei</creatorcontrib><creatorcontrib>Wade, Warren</creatorcontrib><creatorcontrib>Saunders, John</creatorcontrib><creatorcontrib>Bozigian, Haig</creatorcontrib><creatorcontrib>Struthers, R. Scott</creatorcontrib><collection>Istex</collection><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chen</au><au>Wu, Dongpei</au><au>Guo, Zhiqiang</au><au>Xie, Qiu</au><au>Reinhart, Greg J</au><au>Madan, Ajay</au><au>Wen, Jenny</au><au>Chen, Takung</au><au>Huang, Charles Q</au><au>Chen, Mi</au><au>Chen, Yongsheng</au><au>Tucci, Fabio C</au><au>Rowbottom, Martin</au><au>Pontillo, Joseph</au><au>Zhu, Yun-Fei</au><au>Wade, Warren</au><au>Saunders, John</au><au>Bozigian, Haig</au><au>Struthers, R. Scott</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-12-11</date><risdate>2008</risdate><volume>51</volume><issue>23</issue><spage>7478</spage><epage>7485</epage><pages>7478-7485</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19006286</pmid><doi>10.1021/jm8006454</doi><tpages>8</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-12, Vol.51 (23), p.7478-7485 |
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| language | eng |
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| subjects | Animals Biological and medical sciences Caco-2 Cells Cytochrome P-450 CYP3A Inhibitors Drug Discovery Drug Evaluation, Preclinical Hormones. Endocrine system Humans Hydrocarbons, Fluorinated - chemistry Hydrocarbons, Fluorinated - metabolism Hydrocarbons, Fluorinated - pharmacology Macaca fascicularis Male Medical sciences Microsomes, Liver - chemistry Microsomes, Liver - metabolism Molecular Structure Pharmacology. Drug treatments Pyrimidines - chemistry Pyrimidines - metabolism Pyrimidines - pharmacology Receptors, LHRH - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship Time Factors |
| title | Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor |
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