title: Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer.
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.
authors.affiliation: Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. rob.bradbury@astrazeneca.com
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Hales
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Rabow
authors.forename: Graeme E
authors.initials: GE
authors.lastname: Walker
authors.forename: David G
authors.initials: DG
authors.lastname: Acton
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Peter
authors.initials: P
authors.lastname: Ballard
authors.forename: Nigel A N
authors.initials: NA
authors.lastname: Brooks
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: Alan
authors.initials: A
authors.lastname: Girdwood
authors.forename: Urs J
authors.initials: UJ
authors.lastname: Hancox
authors.forename: Owen
authors.initials: O
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Jude
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Loddick
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Mortlock
mesh_terms: D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011724:Pyridazines; D011944:Receptors, Androgen; C062482:pyridazine