Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists |
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Authors: | Guo Chuangxing Pairish Mason Linton Angelica Kephart Susan Ornelas Martha Nagata Asako Burke Benjamin Dong Liming Engebretsen Jon Fanjul Andrea N |
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Affiliation: | Oncology Medicinal Chemistry, Pfizer PharmaTherapeutics R&D, San Diego, CA 92121, USA. alexguo01@gmail.com |
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Abstract: | Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR. |
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