Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists.

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.

[1]  J. Humm,et al.  Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study , 2010, The Lancet.

[2]  C. Sawyers,et al.  Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). , 2010, Journal of medicinal chemistry.

[3]  Armin Ruf,et al.  Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations. , 2010, Journal of molecular biology.

[4]  L. Schweizer,et al.  Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer. , 2009, Cancer research.

[5]  Dafydd R Owen,et al.  Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. , 2009, Bioorganic & medicinal chemistry letters.

[6]  H. Scher,et al.  Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer , 2009, Science.

[7]  H. Scher,et al.  Targeting the androgen receptor pathway in prostate cancer. , 2008, Current opinion in pharmacology.

[8]  Michael A. Galella,et al.  Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists. , 2008, Bioorganic & medicinal chemistry letters.

[9]  H. Cammann,et al.  PSA and new biomarkers within multivariate models to improve early detection of prostate cancer. , 2007, Cancer letters.

[10]  Fernand Labrie,et al.  Comparison of crystal structures of human androgen receptor ligand‐binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity , 2006, Protein science : a publication of the Protein Society.

[11]  K. Kish,et al.  Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[12]  J. Hunt,et al.  Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus. , 2005, Bioorganic & medicinal chemistry letters.

[13]  Hanne Grøn,et al.  Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface , 2004, PLoS biology.

[14]  Thomas S. Scanlan,et al.  Design of thyroid hormone receptor antagonists from first principles , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[15]  M Carlquist,et al.  Structure of the ligand‐binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist , 1999, The EMBO journal.

[16]  Paul A. Rejto,et al.  Reduced Dimensionality in Ligand—Protein Structure Prediction: Covalent Inhibitors of Serine Proteases and Design of Site-Directed Combinatorial Libraries , 1999 .

[17]  P. Schellhammer An update on bicalutamide in the treatment of prostate cancer. , 1999, Expert opinion on investigational drugs.

[18]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[19]  H. Scher,et al.  Steroid hormone withdrawal syndromes. Pathophysiology and clinical significance. , 1997, The Urologic clinics of North America.

[20]  Gennady M Verkhivker,et al.  Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. , 1995, Chemistry & biology.

[21]  F. S. French,et al.  Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique. , 1992, Molecular endocrinology.

[22]  A. Mhatre,et al.  Androgen resistance due to mutation of the androgen receptor. , 1992, Clinical and investigative medicine. Medecine clinique et experimentale.

[23]  R. Vessella,et al.  Molecular determinants of resistance to antiandrogen therapy , 2004, Nature Medicine.