GALAPAGOS, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France.
J Med Chem. 2012 Oct 11;55(19):8225-35. doi: 10.1021/jm300249m. Epub 2012 Sep 25.
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.
一种新型的选择性雄激素受体调节剂支架已经通过对海因类抗雄激素的结构修饰被发现。几种 4-(4-羟苯基)-N-芳基海因类化合物在使用转染了雄激素受体 (AR) 的细胞进行的转激活实验中显示出具有纳摩尔级的部分激动作用。在标准去势雄性大鼠模型中，几种化合物在口服 30mg/kg 剂量后，在升提肌上表现出良好的合成代谢活性，与对前列腺腹侧的雄激素活性分离。(+)-4-[3,4-二甲基-2,5-二氧代-4-(4-羟苯基)咪唑烷-1-基]-2-(三氟甲基)苯甲腈((+)-11b) 显示出很强的升提肌和前列腺腹侧之间的分离的合成代谢效力（A(50) = 0.5mg/kg 对 70mg/kg）。通过使用共激活剂样肽的共结晶实验，研究了两种化合物（包括 (+)-11b）在 AR 配体结合域内的结合模式。两种化合物都结合在同一个位点，AR 的整体结构非常相似。
