The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors
A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, re...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-11, Vol.17 (22), p.6056 |
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| creator | Yuan, Chester St Jean, Jr, David J Liu, Qingyian Cai, Lynn Li, Aiwen Han, Nianhe Moniz, George Askew, Ben Hungate, Randall W Johansson, Lars Tedenborg, Lars Pyring, David Williams, Meredith Hale, Clarence Chen, Michelle Cupples, Rod Zhang, Jiandong Jordan, Steven Bartberger, Michael D Sun, Yaxiong Emery, Maurice Wang, Minghan Fotsch, Christopher |
| description | A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin. |
| format | Article |
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However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.</description><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors</subject><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemistry</subject><subject>Animals</subject><subject>Chlorine - chemistry</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Crystallography, X-Ray</subject><subject>Fluorine - chemistry</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - classification</subject><subject>Thiazoles - pharmacology</subject><issn>0960-894X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1z8tKAzEUgOEslLbWvoLkBQLnNJdJViL10kLBhbNwV3JlItPJMBmF-vQu1NW_--C_IiswCpg24n1Jbmr9AEABQizIEhuDxoBckfu2izTk6stXnC60JLpldsh9HsrcZftd-jLESm2liC7Olu3fHpHmocsuz2Wqt-Q62b7GzV_XpH1-and7dnx9OewejmyUQjKjZHLJeeMahTxE8OBCislrVJKDlDopjFw5bRCkFlLrEJzVwXjbpC3na3L3y46f7hzDaZzy2U6X0_8I_wGKE0M0</recordid><startdate>20071115</startdate><enddate>20071115</enddate><creator>Yuan, Chester</creator><creator>St Jean, Jr, David J</creator><creator>Liu, Qingyian</creator><creator>Cai, Lynn</creator><creator>Li, Aiwen</creator><creator>Han, Nianhe</creator><creator>Moniz, George</creator><creator>Askew, Ben</creator><creator>Hungate, Randall W</creator><creator>Johansson, Lars</creator><creator>Tedenborg, Lars</creator><creator>Pyring, David</creator><creator>Williams, Meredith</creator><creator>Hale, Clarence</creator><creator>Chen, Michelle</creator><creator>Cupples, Rod</creator><creator>Zhang, Jiandong</creator><creator>Jordan, Steven</creator><creator>Bartberger, Michael D</creator><creator>Sun, Yaxiong</creator><creator>Emery, Maurice</creator><creator>Wang, Minghan</creator><creator>Fotsch, Christopher</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20071115</creationdate><title>The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors</title><author>Yuan, Chester ; 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The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.</abstract><cop>England</cop><pmid>17919905</pmid></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2007-11, Vol.17 (22), p.6056 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors 11-beta-Hydroxysteroid Dehydrogenase Type 1 - chemistry Animals Chlorine - chemistry CHO Cells Cricetinae Cricetulus Crystallography, X-Ray Fluorine - chemistry Humans Molecular Structure Rats Structure-Activity Relationship Thiazoles - chemistry Thiazoles - classification Thiazoles - pharmacology |
| title | The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors |
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