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.
MeSH terms
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Administration, Oral
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Androgen Antagonists / pharmacology
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Androgen Receptor Antagonists*
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Anilides / pharmacology
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Chromatography, High Pressure Liquid
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Drug Design
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Humans
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Isoindoles / chemical synthesis
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Isoindoles / pharmacokinetics
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Isoindoles / pharmacology*
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Male
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Molecular Structure
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Nitriles / pharmacology
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Prostatic Neoplasms / blood
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / pathology
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Protein Binding
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Receptors, Androgen / metabolism
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Structure-Activity Relationship
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Tosyl Compounds / pharmacology
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Tumor Cells, Cultured
Substances
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(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
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AR protein, human
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Androgen Antagonists
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Androgen Receptor Antagonists
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Anilides
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Bridged Bicyclo Compounds, Heterocyclic
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Isoindoles
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Nitriles
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Receptors, Androgen
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Tosyl Compounds
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bicalutamide