Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: Hitoshi Yoshino, Haruhiko Sato, Takuya Shiraishi, Kazutaka Tachibana, Takashi Emura, Akie Honma, Nobuyuki Ishikura, Toshiaki Tsunenari, Miho Watanabe, Ayako Nishimoto, Ryo Nakamura, Toshito Nakagawa, Masateru Ohta, Noriyuki Takata, Kentaro Furumoto, Kazuya Kimura, Hiromitsu Kawata

Journal, date & volume: Bioorg. Med. Chem., 2010 Dec 1 , 18, 8150-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21050768

Abstract
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.