Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer

被引：20

作者：

Yoshino, Hitoshi ^{[1
]}

Sato, Haruhiko ^{[1
]}

Shiraishi, Takuya ^{[1
]}

Tachibana, Kazutaka ^{[1
]}

Emura, Takashi ^{[1
]}

Honma, Akie ^{[1
]}

Ishikura, Nobuyuki ^{[1
]}

Tsunenari, Toshiaki ^{[1
]}

Watanabe, Miho ^{[1
]}

Nishimoto, Ayako ^{[1
]}

Nakamura, Ryo ^{[1
]}

Nakagawa, Toshito ^{[1
]}

Ohta, Masateru ^{[1
]}

Takata, Noriyuki ^{[1
]}

Furumoto, Kentaro ^{[1
]}

Kimura, Kazuya ^{[1
]}

Kawata, Hiromitsu ^{[1
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Div Res, Shizuoka 4128513, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 23期

关键词：

Androgen receptor pure antagonist; Prostate cancer; Metabolite; hERG inhibition; ANTIANDROGEN; BICALUTAMIDE; DERIVATIVES; DISCOVERY; FLUTAMIDE;

D O I：

10.1016/j.bmc.2010.10.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：8150 / 8157

页数：8

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