Abstract
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Animals
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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Benzoquinones / chemical synthesis
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Benzoquinones / chemistry
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Benzoquinones / pharmacology
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Biomarkers, Tumor*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Discovery*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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Humans
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Inhibitory Concentration 50
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Lactams, Macrocyclic / chemical synthesis
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacology
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Mice
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Models, Molecular
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Molecular Structure
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Neoplasms / drug therapy
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Xenograft Model Antitumor Assays
Substances
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Amines
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Benzamides
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Benzoquinones
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Biomarkers, Tumor
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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Macrocyclic Compounds
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geldanamycin