Abstract
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Biomarkers / metabolism*
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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 Design*
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Fluorescent Dyes / chemical synthesis
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Fluorescent Dyes / chemistry
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Fluorescent Dyes / pharmacology
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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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Models, Molecular
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Molecular Structure
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ortho-Aminobenzoates / chemical synthesis
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology
Substances
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Antineoplastic Agents
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Biomarkers
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Fluorescent Dyes
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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ortho-Aminobenzoates
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anthranilamide