Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer |
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Authors: | Bradbury Robert H Hales Neil J Rabow Alfred A Walker Graeme E Acton David G Andrews David M Ballard Peter Brooks Nigel A N Colclough Nicola Girdwood Alan Hancox Urs J Jones Owen Jude David Loddick Sarah A Mortlock Andrew A |
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Affiliation: | Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. rob.bradbury@astrazeneca.com |
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Abstract: | 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. |
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Keywords: | Prostate cancer Androgen receptor downregulator Androgen antagonist |
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