Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists |
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| Authors: | Salvati Mark E Balog Aaron Shan Weifang Rampulla Richard Giese Soren Mitt Tom Furch Joseph A Vite Gregory D Attar Ricardo M Jure-Kunkel Maria Geng Jieping Rizzo Cheryl A Gottardis Marco M Krystek Stanley R Gougoutas Jack Galella Michael A Obermeier Mary Fura Aberra Chandrasena Gamini |
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| Institution: | Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. mark.salvati@bms.co |
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| Abstract: | A novel series of 2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound 3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model. |
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