title: Synthesis of potent and tissue-selective androgen receptor modulators (SARMs): 2-(2,2,2)-Trifluoroethyl-benzimidazole scaffold.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Drug Discovery, 665 Stockton Drive, Exton, PA 19341, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Ng
authors.forename: James C
authors.initials: JC
authors.lastname: Lanter
authors.forename: Vernon C
authors.initials: VC
authors.lastname: Alford
authors.forename: George F
authors.initials: GF
authors.lastname: Allan
authors.forename: Tifanie
authors.initials: T
authors.lastname: Sbriscia
authors.forename: Scott G
authors.initials: SG
authors.lastname: Lundeen
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: 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
chemical_list: C519770:2-(2,2,2)-trifluoroethyl-benzimidazole; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001562:Benzimidazoles; D007202:Indicators and Reagents; D011944:Receptors, Androgen