Abstract
A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.
MeSH terms
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Administration, Oral
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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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Binding, Competitive
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Biological Availability
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Blood Proteins / metabolism
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Cell Line, Tumor
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Cell Membrane Permeability
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Drug Screening Assays, Antitumor
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Drug Stability
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Female
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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Humans
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Hydrophobic and Hydrophilic Interactions
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In Vitro Techniques
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Male
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Melanoma / drug therapy
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Melanoma / pathology
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Models, Molecular
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Neoplasm Transplantation
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Protein Binding
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Rats
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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2-amino-4-(4-chloro-2-(2-(4-fluoro-1H-pyrazol-1-yl)ethoxy)-6-methylphenyl)-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo(3,4-d)pyrimidine-6-carboxamide
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Antineoplastic Agents
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Blood Proteins
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HSP90 Heat-Shock Proteins
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Pyrazoles
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Pyrimidines