Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists

Bioorg Med Chem. 2012 Jan 1;20(1):422-34. doi: 10.1016/j.bmc.2011.10.067. Epub 2011 Oct 28.


A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

MeSH terms

  • Amino Acid Substitution
  • Androgen Receptor Antagonists / chemical synthesis*
  • Androgen Receptor Antagonists / pharmacology
  • Androgen Receptor Antagonists / therapeutic use
  • Androgen Receptor Antagonists / toxicity
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Drug Design*
  • Drug Resistance, Neoplasm
  • Humans
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Nude
  • Mutation
  • Prostatic Neoplasms / drug therapy
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use
  • Receptors, Androgen / chemistry*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Transplantation, Heterologous


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