Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists

Bioorg Med Chem Lett. 2005 Jan 17;15(2):271-6. doi: 10.1016/j.bmcl.2004.10.085.

Mark E Salvati ¹, Aaron Balog, Weifang Shan, Donna D Wei, Dacia Pickering, Ricardo M Attar, Jieping Geng, Cheryl A Rizzo, Marco M Gottardis, Roberto Weinmann, Stanley R Krystek, John Sack, Yongmi An, Kevin Kish

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Affiliation

1 Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. [email protected]

PMID: 15603938 DOI: 10.1016/j.bmcl.2004.10.085

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.

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