Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer

被引：39
|
作者：
Bradbury, Robert H. [1 ]
Hales, Neil J. [1 ]
Rabow, Alfred A. [1 ]
Walker, Graeme E. [1 ]
Acton, David G. [1 ]
Andrews, David M. [1 ]
Ballard, Peter [1 ]
Brooks, Nigel A. N. [1 ]
Colclough, Nicola [1 ]
Girdwood, Alan [1 ]
Hancox, Urs J. [1 ]
Jones, Owen [1 ]
Jude, David [1 ]
Loddick, Sarah A. [1 ]
Mortlock, Andrew A. [1 ]
机构：
[1] AstraZeneca, Oncol IMed, Macclesfield SK10 4TG, Cheshire, England
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 18期
关键词：
Prostate cancer; Androgen receptor downregulator; Androgen antagonist; ANTIANDROGEN; ANTAGONISTS; FULVESTRANT;
D O I：
10.1016/j.bmcl.2011.06.122
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]3-(trifluoromethyl)[1,2,4] triazolo[4,3-b] pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5442 / 5445
页数：4
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