Synthesis and Structure鈥揂ctivity Relationship Studies of Novel Dihydropyridones as Androgen Receptor Modulators

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• 作者：Antonella Pepe ; Michael Pamment ; Yeong Sang Kim ; Sunmin Lee ; Min-Jung Lee ; Kristin Beebe ; Anton Filikov ; Len Neckers ; Jane B. Trepel ; Sanjay V. Malhotra
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8280-8297
• 全文大小：875K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure鈥揳ctivity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor鈥搇igand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens.