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

Christoph W Zapf; Jonathan D Bloom; Jamie L McBean; Russell G Dushin; Thomas Nittoli; Charles Ingalls; Alan G Sutherland; John P Sonye; Clark N Eid; Jennifer Golas; Hao Liu; Frank Boschelli; Yongbo Hu; Erik Vogan; Jeremy I Levin

doi:10.1016/j.bmcl.2011.02.101

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

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2278-82. doi: 10.1016/j.bmcl.2011.02.101. Epub 2011 Feb 28.

Authors

Christoph W Zapf¹, Jonathan D Bloom, Jamie L McBean, Russell G Dushin, Thomas Nittoli, Charles Ingalls, Alan G Sutherland, John P Sonye, Clark N Eid, Jennifer Golas, Hao Liu, Frank Boschelli, Yongbo Hu, Erik Vogan, Jeremy I Levin

Affiliation

¹ Medicinal Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA. [email protected]

PMID: 21420297
DOI: 10.1016/j.bmcl.2011.02.101

Abstract

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacology
Binding Sites
Cell Line, Tumor
Cell Proliferation
Computer Simulation
Crystallography, X-Ray
Drug Design
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Protein Binding
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzamides
HSP90 Heat-Shock Proteins
benzamide