[2.2.1]-Bicyclic sultams as potent androgen receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 23; pp. 5707 - 5711
• Main Authors: Shan, Weifang, Balog, Aaron, Nation, Andrew, Zhu, Xiao, Chen, Jing, Cvijic, Mary Ellen, Geng, Jieping, Rizzo, Cheryl A., Spires, Thomas, Attar, Ricardo M., Obermeier, Mary, Traeger, Sarah, Dai, Jun, Zhang, Yingru, Galella, Michael, Trainor, George, Vite, Gregory D., Gavai, Ashvinikumar V.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2016; Elsevier
• Subjects: Administration, Oral; Androgen receptor antagonist; Androgen Receptor Antagonists - chemistry; Androgen Receptor Antagonists - pharmacokinetics; Androgen Receptor Antagonists - pharmacology; Animals; Bridged Bicyclo Compounds - administration & dosage; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - pharmacokinetics; Bridged Bicyclo Compounds - pharmacology; Cancer; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Life Sciences & Biomedicine; Models, Molecular; Naphthalenesulfonates - administration & dosage; Naphthalenesulfonates - chemistry; Naphthalenesulfonates - pharmacokinetics; Naphthalenesulfonates - pharmacology; Nuclear hormone receptor; Pharmacokinetics and pharmacodynamics; Pharmacology & Pharmacy; Physical Sciences; Rats; Receptors, Androgen - metabolism; Science & Technology; Structure-Activity Relationship; Pharmacokinetics and pharmacodynamics; Nuclear hormone receptor; Androgen receptor antagonist; Cancer; BMS-641988; RESISTANT PROSTATE-CANCER; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.10.059

This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing. [Display omitted] This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.