Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer

  • Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8. doi: 10.1016/j.bmcl.2013.02.056.
Robert H Bradbury  1 ,  David G Acton ,  Nicola L Broadbent ,  A Nigel Brooks ,  Gregory R Carr ,  Glenn Hatter ,  Barry R Hayter ,  Kathryn J Hill ,  Nicholas J Howe ,  Rhys D O Jones ,  David Jude ,  Scott G Lamont ,  Sarah A Loddick ,  Heather L McFarland ,  Zaieda Parveen ,  Alfred A Rabow ,  Gorkhn Sharma-Singh ,  Natalie C Stratton ,  Andrew G Thomason ,  Dawn Trueman ,  Graeme E Walker ,  Stuart L Wells ,  Joanne Wilson ,  J Matthew Wood
Affiliations
  • 1. Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. [email protected]
PMID: 23466225 DOI: 10.1016/j.bmcl.2013.02.056
Abstract

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead Androgen Receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant Prostate Cancer.

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