Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists

Bioorg Med Chem. 2010 May 1;18(9):3159-68. doi: 10.1016/j.bmc.2010.03.036. Epub 2010 Mar 19.

Abstract

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of hormone refractory prostate cancer. CH4933468 (32d) with a sulfonamide side chain not only exhibited antagonistic activity with no agonistic activity in the reporter gene assay but also inhibited the growth of bicalutamide-resistant cell lines. This compound also inhibited tumor growth of the LNCaP xenograft in mice dose-dependently.

MeSH terms

  • Androgen Antagonists* / chemical synthesis
  • Androgen Antagonists* / chemistry
  • Androgen Antagonists* / pharmacology
  • Animals
  • Antineoplastic Agents, Hormonal* / chemical synthesis
  • Antineoplastic Agents, Hormonal* / chemistry
  • Antineoplastic Agents, Hormonal* / pharmacology
  • Carboxylic Acids* / chemical synthesis
  • Carboxylic Acids* / chemistry
  • Carboxylic Acids* / pharmacology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, SCID
  • Molecular Structure
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / therapeutic use
  • Prostatic Neoplasms / drug therapy
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / therapeutic use
  • Thiohydantoins / chemical synthesis
  • Thiohydantoins / chemistry
  • Thiohydantoins / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • CH4933468
  • Carboxylic Acids
  • Nitriles
  • Sulfonamides
  • Thiohydantoins