Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists

被引：25

作者：

Salvati, Mark E. ^{[1
]}

Balog, Aaron ^{[1
]}

Shan, Weifang ^{[1
]}

Rampulla, Richard ^{[1
]}

Giese, Soren ^{[1
]}

Mitt, Tom ^{[1
]}

Furch, Joseph A. ^{[1
]}

Vite, Gregory D. ^{[1
]}

Attar, Ricardo M. ^{[1
]}

Jure-Kunkel, Maria ^{[2
]}

Geng, Jieping ^{[2
]}

Rizzo, Cheryl A. ^{[2
]}

Gottardis, Marco M. ^{[2
]}

Krystek, Stanley R. ^{[3
]}

Gougoutas, Jack ^{[3
]}

Galella, Michael A. ^{[3
]}

Obermeier, Mary ^{[4
]}

Fura, Aberra ^{[4
]}

Chandrasena, Gamini ^{[4
]}

机构：

[1] Bristol Myers Squibb Pharmaceut Res & Dev, Dept Oncol Chem, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Pharmaceut Res & Dev, Dept Discovery Biol, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Pharmaceut Res & Dev, Dept Macromol Struct, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Pharmaceut Res & Dev, Pharmaceut Candidate Optimizat Dept, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 06期

关键词：

androgen receptor; prostate cancer; AR antagonist; CWR22R; 2.2.1]-oxabicyclo;

D O I：

10.1016/j.bmcl.2008.02.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3 alpha S-(3 alpha alpha,4 beta, 5 beta, 7 beta, 7 alpha alpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model. Published by Elsevier Ltd.

引用

页码：1910 / 1915

页数：6

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