Preparation of 4-aryl-2-trifluoromethylbenzonitrile derivatives as androgen receptor antagonists for topical suppression of sebum production.
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%).
Van Camp
Jennifer A
JA
Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. jennifer_vancamp@yahoo.com
Hu
Lain-Yen
LY
Kostlan
Catherine
C
Lefker
Bruce
B
Li
Jie
J
Mitchell
Lorna
L
Wang
Zhi
Z
Yue
Wen-Song
WS
Carroll
Matthew
M
Dettling
Danielle
D
Du
Daniel
D
Pocalyko
David
D
Wade
Kimberly
K
D059002:Androgen Receptor Antagonists; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008745:Methylation; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism*; D012629:Sebum / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D059002:Androgen Receptor Antagonists; D009570:Nitriles; D011944:Receptors, Androgen; D005461:Fluorine; C014356:benzonitrile