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

Authors :: Bradbury RH
Hales NJ
Rabow AA
Walker GE
Acton DG
Andrews DM
Ballard P
Brooks NA
Colclough N
Girdwood A
Hancox UJ
Jones O
Jude D
Loddick SA
Mortlock AA
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Sep 15; Vol. 21 (18), pp. 5442-5. Date of Electronic Publication: 2011 Jul 02.
Publication Year :: 2011
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.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Subjects :: Dose-Response Relationship, Drug
Down-Regulation drug effects
Humans
Ligands
Male
Models, Molecular
Molecular Structure
Molecular Weight
Prostatic Neoplasms metabolism
Pyridazines chemical synthesis
Pyridazines chemistry
Stereoisomerism
Structure-Activity Relationship
Prostatic Neoplasms drug therapy
Pyridazines pharmacology
Receptors, Androgen metabolism

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