Journal of Medicinal Chemistry p. 8225 - 8235,11 (2012)
Update date:2022-08-02
Topics:
Nique, Francois
Hebbe, Severine
Peixoto, Christophe
Annoot, Denis
Lefrancois, Jean-Michel
Duval, Eric
Michoux, Laurence
Triballeau, Nicolas
Lemoullec, Jean-Michel
Mollat, Patrick
Minet, Dominique
Clement-Lacroix, Philippe
Robin-Jagerschmidt, Catherine
Fleury, Damien
Guedin, Denis
Deprez, Pierre
Thauvin, Maxime
Prange, Thierry
A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl] -2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A 50 = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.
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