Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists

  • J Med Chem. 2011 Nov 10;54(21):7693-704. doi: 10.1021/jm201059s.
Chuangxing Guo  1 ,  Angelica Linton ,  Susan Kephart ,  Martha Ornelas ,  Mason Pairish ,  Javier Gonzalez ,  Samantha Greasley ,  Asako Nagata ,  Benjamin J Burke ,  Martin Edwards ,  Natilie Hosea ,  Ping Kang ,  Wenyue Hu ,  Jon Engebretsen ,  David Briere ,  Manli Shi ,  Hovik Gukasyan ,  Paul Richardson ,  Kevin Dack ,  Toby Underwood ,  Patrick Johnson ,  Andrew Morell ,  Robert Felstead ,  Hidetoshi Kuruma ,  Hiroaki Matsimoto ,  Amina Zoubeidi ,  Martin Gleave ,  Gerrit Los ,  Andrea N Fanjul
Affiliations
  • 1. Pfizer Worldwide Research & Development , San Diego, CA 92121, USA. [email protected]
PMID: 21936524 DOI: 10.1021/jm201059s
Abstract

An aryloxy tetramethylcyclobutane was identified as a novel template for Androgen Receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a Castration-Resistant Prostate Cancer (CRPC) animal model.

Products