Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer

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• 作者：James K. Johnson ; Erin M. Skoda ; Jianhua Zhou ; Erica Parrinello ; Dan Wang ; Katherine O’Malley ; Benjamin R. Eyer ; Mustafa Kazancioglu ; Kurtis Eisermann ; Paul A. Johnston ; Joel B. Nelson ; Zhou Wang ; Peter Wipf
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：7
• 期：8
• 页码：785-790
• 全文大小：394K
• 年卷期：0
• ISSN：1948-5875

文摘

After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure–activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.