Abstract
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
MeSH terms
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Acetates / chemical synthesis*
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Acetates / pharmacokinetics
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Acetates / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Hepatocytes / metabolism
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Humans
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Macaca fascicularis
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Conformation
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Neoplasm Transplantation
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Piperidones / chemical synthesis*
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Piperidones / pharmacokinetics
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Piperidones / pharmacology
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Protein Binding
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Transplantation, Heterologous
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Tumor Suppressor Protein p53 / metabolism*
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rho GTP-Binding Proteins / biosynthesis
Substances
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2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
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Acetates
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Antineoplastic Agents
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Piperidones
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2
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rho GTP-Binding Proteins