Design of oxobenzimidazoles and oxindoles as novel androgen receptor antagonists

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.Figure optionsDownload as PowerPoint slide

A series of novel, non-steroidal AR antagonists were discovered through SBDD of AR LBD binders that have the potential to force AR helix 12 (H12) movement. Aqueous solubility was improved by designing ligand-efficient molecules with reduced planarity.Figure optionsDownload as PowerPoint slide