Synthesis of potent and tissue-selective androgen receptor modulators (SARMs): 2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold.
The synthesis and in vivo SAR of 2-(2,2,2)-trifluoroethyl-benzimidazoles are described. Prostate antagonism and/or levator ani agonism can be modulated by varying the substitution at the 2-position of 5,6-dichloro-benzimidazoles. Potent androgen agonists on the muscle were discovered that strongly bind to the androgen receptor (2-17 nM) and show potent in vivo efficacy (0.03-0.11 mg/day). True SARMs showing both prostate antagonism and levator ani agonism were revealed.
Ng
Raymond A
RA
Johnson & Johnson Pharmaceutical Research and Development, LLC, Drug Discovery, 665 Stockton Drive, Exton, PA 19341, USA.
Lanter
James C
JC
Alford
Vernon C
VC
Allan
George F
GF
Sbriscia
Tifanie
T
Lundeen
Scott G
SG
Sui
Zhihua
Z
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D001562:Benzimidazoles / Q000819:agonists / Q000037:antagonists & inhibitors / Q000138:chemical synthesis*; D004305:Dose-Response Relationship, Drug; D007202:Indicators and Reagents; D008297:Male; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects*; D013329:Structure-Activity Relationship
C519770:2-(2,2,2)-trifluoroethyl-benzimidazole; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001562:Benzimidazoles; D007202:Indicators and Reagents; D011944:Receptors, Androgen