Design, synthesis, and biological evaluation of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives as novel androgen receptor antagonists

Bioorg Med Chem. 2013 Jan 1;21(1):70-83. doi: 10.1016/j.bmc.2012.11.001. Epub 2012 Nov 12.


We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R(2)) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R(1)) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide.

MeSH terms

  • Androgen Receptor Antagonists / chemistry*
  • Androgen Receptor Antagonists / therapeutic use*
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / therapeutic use*
  • Castration
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Male
  • Mice
  • Models, Molecular
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / surgery
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / surgery
  • Pyrrolidines / chemistry*
  • Pyrrolidines / therapeutic use*
  • Receptors, Androgen / metabolism
  • Xenograft Model Antitumor Assays


  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Pyrrolidines
  • Receptors, Androgen