Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.
A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
Chugai Pharmaceutical Co., Ltd, Gotemba, Shizuoka, Japan. yoshinohts@chugai-pharm.co.jp
Hitoshi
H
Yoshino
Haruhiko
H
Sato
Takuya
T
Shiraishi
Kazutaka
K
Tachibana
Takashi
T
Emura
Akie
A
Honma
Nobuyuki
N
Ishikura
Toshiaki
T
Tsunenari
Miho
M
Watanabe
Ayako
A
Nishimoto
Ryo
R
Nakamura
Toshito
T
Nakagawa
Masateru
M
Ohta
Noriyuki
N
Takata
Kentaro
K
Furumoto
Kazuya
K
Kimura
Hiromitsu
H
Kawata
D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002369:Castration; D004285:Dogs; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D010672:Phenytoin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013867:Thiohydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D014183:Transplantation, Heterologous
C556284:6-(3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)pyridine-2-sulfonic acid amide; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; D011944:Receptors, Androgen; D013449:Sulfonamides; D013867:Thiohydantoins; C073336:diphenylthiohydantoin; D010672:Phenytoin