title: Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.
abstract: 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.
authors.affiliation: Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. mark.salvati@bms.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Salvati
authors.forename: Aaron
authors.initials: A
authors.lastname: Balog
authors.forename: Weifang
authors.initials: W
authors.lastname: Shan
authors.forename: Donna D
authors.initials: DD
authors.lastname: Wei
authors.forename: Dacia
authors.initials: D
authors.lastname: Pickering
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Jieping
authors.initials: J
authors.lastname: Geng
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Rizzo
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Roberto
authors.initials: R
authors.lastname: Weinmann
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Krystek
authors.forename: John
authors.initials: J
authors.lastname: Sack
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000726:Androgen Antagonists; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D020033:Protein Isoforms; D011944:Receptors, Androgen