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

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Yoshino H, Sato H, Shiraishi T, Tachibana K, Emura T, Honma A, Ishikura N, Tsunenari T, Watanabe M, Nishimoto A, Nakamura R, Nakagawa T, Ohta M, Takata N, Furumoto K, Kimura K, Kawata H

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. Epub 2010 Oct 15.

PubMed ID

21050768 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Bicalutamide	Androgen receptor	IC 50 (nM)	200	N/A	N/A	Details
Bicalutamide	Androgen receptor	IC 50 (nM)	600	N/A	N/A	Details