(+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3- yl]piperazine-1-carboxamide (YM580) as an Orally Potent and Peripherally Selective Nonsteroidal Androgen Receptor Antagonist

J Med Chem. 2006 Jan 26;49(2):716-26. doi: 10.1021/jm050293c.

Abstract

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.

MeSH terms

  • Administration, Oral
  • Androgen Antagonists / adverse effects
  • Androgen Antagonists / chemical synthesis*
  • Androgen Antagonists / pharmacology
  • Androgen Receptor Antagonists*
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Humans
  • Hypothalamus / metabolism
  • Male
  • Organ Size / drug effects
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Prostate / anatomy & histology
  • Prostate / drug effects
  • Prostate / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats
  • Receptors, Androgen / genetics
  • Stereoisomerism
  • Structure-Activity Relationship
  • Testosterone / blood
  • Tissue Distribution
  • Transcription, Genetic

Substances

  • 4-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dimethyl-N-(6-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxamide
  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Piperazines
  • Pyridines
  • Receptors, Androgen
  • Testosterone