title: Biological properties of androgen receptor pure antagonist for treatment of castration-resistant prostate cancer: optimization from lead compound to CH5137291.
abstract: BACKGROUND
  Castration-resistant prostate cancer (CRPC) is still dependent on androgen receptor (AR) signaling. We previously reported that a novel nonsteroidal AR pure antagonist, CH4933468, which is a thiohydantoin derivative with a sulfonamide side chain, provided in vitro proof of concept but did not in vivo.
  
  
  METHODS
  We developed other derivatives, CH5137291, CH5138514, and CH5166623, and their pharmacological properties were compared with CH4933468 and bicalutamide. Agonist/antagonist activities in AR-mediated transactivation, cell proliferation against LNCaP and LNCaP-BC2, and AR translocation were evaluated. Agonist metabolite was monitored in liver microsomes and in pharmacokinetics experiments. Antitumor activities in CRPC xenograft models were examined using LNCaP-BC2 and VCaP-CRPC.
  
  
  RESULTS
  All CH compounds completely inhibited AR-mediated transactivation and proliferation of LNCaP and LNCaP-BC2. In contrast bicalutamide showed a partial inhibition of AR-mediated transactivation and a proliferation of LNCaP-BC2. AR translocation to nucleus was inhibited by CH compounds, but stimulated by bicalutamide. In the LNCaP-BC2 xenograft model, however, only CH5137291 showed significant inhibition of plasma PSA level and antitumor activity. The other three CH compounds were metabolized to their core structure which had agonist activity. CH5137291 also exhibited antitumor activity in a VCaP-CRPC xenograft model, but bicalutamide did not.
  
  
  CONCLUSIONS
  The molecular mechanism of the CH compounds, inhibition of AR translocation, was different from bicalutamide and this action could contribute to AR pure antagonist activity. Agonist metabolite diminished the antitumor activity of AR pure antagonist. CH5137291 exhibited antitumor activity in LNCaP-BC2 and VCaP-CRPC xenograft models, suggesting that the compound has potential for the treatment of CRPC.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan. kawatahrm@chugai-pharm.co.jp
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kawata
authors.forename: Shinichi
authors.initials: S
authors.lastname: Arai
authors.forename: Toshito
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ishikura
authors.forename: Ayako
authors.initials: A
authors.lastname: Nishimoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Takuya
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tachibana
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakamura
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sato
mesh_terms: D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D059002:Androgen Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000813:Anilides / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007854:Lead; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000601:surgery*; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013867:Thiohydantoins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous
chemical_list: C556284:6-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)pyridine-2-sulfonic acid amide; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; C561305:CH 5138514; C561306:CH 5166623; C551969:CH4933468; D002219:Carbamates; D009570:Nitriles; D011944:Receptors, Androgen; D013449:Sulfonamides; D013867:Thiohydantoins; D014105:Tosyl Compounds; D007854:Lead; C053541:bicalutamide