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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Androgen Receptor Antagonists / chemical synthesis*
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Androgen Receptor Antagonists / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / pharmacology
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Cell Line, Tumor
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Drug Design
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Drug Discovery
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Ligands
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Male
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Models, Molecular
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Prostatic Neoplasms
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptors, Androgen / chemistry*
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Receptors, Androgen / metabolism
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Solubility
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Structure-Activity Relationship
Substances
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Androgen Receptor Antagonists
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Antineoplastic Agents
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Benzimidazoles
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Indoles
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Ligands
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Receptors, Androgen