Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists
A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2005-01, Vol.15 (2), p.271-276 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 15 |
| creator | SALVATI, Mark E BALOG, Aaron KRYSTEK, Stanley R SACK, John YONGMI AN KISH, Kevin WEIFANG SHAN WEI, Donna D PICKERING, Dacia ATTAR, Ricardo M JIEPING GENG RIZZO, Cheryl A GOTTARDIS, Marco M WEINMANN, Roberto |
| description | A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule. |
| doi_str_mv | 10.1016/j.bmcl.2004.10.085 |
| format | Article |
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Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.</description><subject>Androgen Antagonists - chemical synthesis</subject><subject>Androgen Antagonists - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Hormones. Endocrine system</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Isoforms</subject><subject>Receptors, Androgen - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE9r3DAQxUVISbbbfIEcii8JLUTbkfXH8jGEthsI9JAUejOSPNpo8VobST7k28dLluYyA4_33jA_Qi4ZrBgw9WO7sjs3rGoAMQsr0PKELJhQgnIB8pQsoFVAdSv-nZPPOW8BmAAhzsg5kwp4y_WCvDyWNLkyJaysydhXZr9P0bjnqsSqPGPVYw6bsYq-ssG9uiE4ytY05BjGPg5I2Q3_Vq-_0z7E8X_H2Ke4wbFK6HBfYpqVYjZxDLnkL-STN0PGi-Nekr-_fj7drenDn9_3d7cP1HHOCmXIRW2lB4229k3NDGuxcdKgkD3z2igFDePScd-A11xa1HXjrBTWcdNrviTX773zPy8T5tLtQnY4DGbEOOVONfMdNo8lqd-NLsWcE_pun8LOpNeOQXcA3W27A-juAPqgzaDn0Ndj-2R32H9EjmRnw9XRYLIzg09mdCF_-BRvoVaavwEps4fm</recordid><startdate>20050117</startdate><enddate>20050117</enddate><creator>SALVATI, Mark E</creator><creator>BALOG, Aaron</creator><creator>KRYSTEK, Stanley R</creator><creator>SACK, John</creator><creator>YONGMI AN</creator><creator>KISH, Kevin</creator><creator>WEIFANG SHAN</creator><creator>WEI, Donna D</creator><creator>PICKERING, Dacia</creator><creator>ATTAR, Ricardo M</creator><creator>JIEPING GENG</creator><creator>RIZZO, Cheryl A</creator><creator>GOTTARDIS, Marco M</creator><creator>WEINMANN, Roberto</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>7X8</scope></search><sort><creationdate>20050117</creationdate><title>Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists</title><author>SALVATI, Mark E ; BALOG, Aaron ; KRYSTEK, Stanley R ; SACK, John ; YONGMI AN ; KISH, Kevin ; WEIFANG SHAN ; WEI, Donna D ; PICKERING, Dacia ; ATTAR, Ricardo M ; JIEPING GENG ; RIZZO, Cheryl A ; GOTTARDIS, Marco M ; WEINMANN, Roberto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-1e342b5f08eb2f721a19e7c5ae45d1f8a6607135c3f70f835be827cb54bc3ad83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Androgen Antagonists - chemical synthesis</topic><topic>Androgen Antagonists - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Hormones. Endocrine system</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Medical sciences</topic><topic>Pharmacology. 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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Androgen Antagonists - chemical synthesis Androgen Antagonists - pharmacology Biological and medical sciences Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - pharmacology Hormones. Endocrine system Indoles - chemistry Indoles - pharmacology Medical sciences Pharmacology. Drug treatments Protein Isoforms Receptors, Androgen - metabolism Structure-Activity Relationship Tumor Cells, Cultured |
| title | Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists |
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