Design and synthesis of an array of selective androgen receptor modulators.
We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males.
Trump
Ryan P
RP
GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. ryan.p.trump@gsk.com
Blanc
Jean-Baptiste E
JB
Stewart
Eugene L
EL
Brown
Peter J
PJ
Caivano
Matilde
M
Gray
David W
DW
Hoekstra
William J
WJ
Willson
Timothy M
TM
Han
Bajin
B
Turnbull
Philip
P
D000465:Algorithms; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D000882:Haplorhini; D009682:Magnetic Resonance Spectroscopy; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
D059002:Androgen Receptor Antagonists; D000728:Androgens; D009570:Nitriles; C045271:4-aminobenzonitrile