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

详细信息    查看全文

• 作者：Robert H. Bradbury^† ; ; ^a ; ^{rob.bradbury@astrazeneca.com"" rel=""nofollow} ; Neil J. Hales^† ; ; ^a ; Alfred A. Rabow^† ; ; ^a ; Graeme E. Walker^† ; ; ^a ; David G. Acton^a ; David M. Andrews^a ; Peter Ballard^a ; Nigel A.N. Brooks^a ; Nicola Colclough^a ; Alan Girdwood^a ; Urs J. Hancox^a ; Owen Jones^a ; David Jude^a ; Sarah A. Loddick^a ; Andrew A. Mortlock^a
• 关键词：Prostate cancer ; Androgen receptor downregulator ; Androgen antagonist
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：21
• 期：18
• 页码：5442-5445
• 全文大小：448 K

文摘

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.