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.
Christoph W Zapf  1 ,  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
Affiliations
  • 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.