Structure-activity relationships of bioisosteric replacement of the carboxylic acid in novel androgen receptor pure antagonists.
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.
Yoshino
Hitoshi
H
Research Division, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan. yoshinohts@chugai-pharm.co.jp
Sato
Haruhiko
H
Tachibana
Kazutaka
K
Shiraishi
Takuya
T
Nakamura
Mitsuaki
M
Ohta
Masateru
M
Ishikura
Nobuyuki
N
Nagamuta
Masahiro
M
Onuma
Etsuro
E
Nakagawa
Toshito
T
Arai
Shinichi
S
Ahn
Koo-Hyeon
KH
Jung
Kyung-Yun
KY
Kawata
Hiromitsu
H
D000726:Androgen Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C551969:CH4933468; D002264:Carboxylic Acids; D009570:Nitriles; D013449:Sulfonamides; D013867:Thiohydantoins