Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure–activity relationship information was ob...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (8), p.2278-2282
Main Authors: Zapf, Christoph W., Bloom, Jonathan D., McBean, Jamie L., Dushin, Russell G., Nittoli, Thomas, Ingalls, Charles, Sutherland, Alan G., Sonye, John P., Eid, Clark N., Golas, Jennifer, Liu, Hao, Boschelli, Frank, Hu, Yongbo, Vogan, Erik, Levin, Jeremy I.
Format: Article
Language:English
Subjects:
aniline
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacology
Binding Sites
Biological and medical sciences
Buchwald–Hartwig cyclization
Cell Line, Tumor
Cell Proliferation
Chaperon inhibitors
Computer Simulation
Crystallography, X-Ray
Drug Design
General aspects
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Hsp90 inhibitors
Humans
Macrocycles
Medical sciences
N-terminal ATP-binding site
nitrogen
ortho-Aminobenzamides
Pharmacology. Drug treatments
physical properties
Protein Binding
Structure-Activity Relationship
structure-activity relationships
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Description
Summary:A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure–activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.02.101