Abstract
Guided by structure-based drug design, modification of the 1,4-benzodiazepin-2,5-dione lead compound 1 resulted in the discovery of 19, a potent and orally bioavailable antagonist of the HDM2-p53 protein-protein interaction (FP IC50 = 0.7 microM, F approximately 100%).
MeSH terms
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Alkylation
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Animals
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Benzodiazepines / chemical synthesis
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Benzodiazepines / chemistry*
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Cell Line, Tumor
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Cell Membrane Permeability
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Design*
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Humans
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Mice
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Models, Molecular
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Molecular Structure
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Pentanoic Acids / chemistry
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Protein Binding
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Pentanoic Acids
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Tumor Suppressor Protein p53
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Benzodiazepines
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Bz-423