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

  • Bioorg Med Chem. 2010 Dec 1;18(23):8150-7. doi: 10.1016/j.bmc.2010.10.023.
Hitoshi Yoshino  1 ,  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
Affiliations
PMID: 21050768 DOI: 10.1016/j.bmc.2010.10.023
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.

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