Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D
Centre de Recherches Roussel UCLAF, Romainville, France.
J Steroid Biochem Mol Biol. 1994 Jan;48(1):111-9. doi: 10.1016/0960-0760(94)90257-7.
New N-substituted arylthiohydantoin antiandrogens were synthesized. These compounds presented exceptionally high relative binding affinities (RBAs) for the rat androgen receptor (AR): up to 3 times that of testosterone (T) and 100 times the RBAs of non-steroidal antiandrogens such as flutamide, Casodex and Anandron. Furthermore, unlike available markers for AR, they were totally devoid of any binding to the other steroid receptors. RU 59063, the molecule with the highest RBA, was tritiated. When it was compared to [3H]T for the assay of rat, mouse, hamster and human AR, it gave rise to the same number of binding sites but its K alpha (6 x 10(9) M-1) for rat and human AR were, respectively 3 and 8 times higher than that of T. Moreover RU 59063, unlike T, was devoid of any specific binding to human plasma. In vivo, these compounds displayed antiandrogenic activity while being devoid of any agonistic effect. Thus, RU 56187, given orally in castrated male animals, prevented in a dose-dependent manner the effects of 3 mg/kg testosterone propionate (TP) on mouse renal ornithine decarboxylase (acute test) and of 0.5 mg/kg TP on rat prostate weight (chronic test). In these two models, its ED50 was 0.6 and 1 mg/kg, respectively. In the intact rat, when given alone, it inhibited dose-dependently the effect of endogenous androgens on the seminal vesicles (ED50 approximately 1 mg/kg) and prostate (ED50 approximately 3 mg/kg) weights. These results suggest that these new compounds may be useful as specific markers for the androgen receptor as well as for the treatment of androgen-dependent diseases or disorders such as prostate cancer, acne, hirsutism and male pattern baldness.
合成了新型N-取代芳硫基乙内酰脲抗雄激素。这些化合物对大鼠雄激素受体（AR）表现出极高的相对结合亲和力（RBA）：高达睾酮（T）的3倍，是非甾体抗雄激素如氟他胺、比卡鲁胺和安体舒通RBA的100倍。此外，与现有的AR标记物不同，它们与其他类固醇受体完全没有结合。对具有最高RBA的分子RU 59063进行了氚标记。在用于测定大鼠、小鼠、仓鼠和人AR时，将其与[3H]T比较，发现其结合位点数量相同，但大鼠和人AR的Kα（6×10⁹ M⁻¹）分别比T高3倍和8倍。此外，与T不同，RU 59063与人血浆没有任何特异性结合。在体内，这些化合物表现出抗雄激素活性，同时没有任何激动作用。因此，给去势雄性动物口服RU 56187，能以剂量依赖性方式预防3 mg/kg丙酸睾酮（TP）对小鼠肾鸟氨酸脱羧酶的作用（急性试验）以及0.5 mg/kg TP对大鼠前列腺重量的作用（慢性试验）。在这两种模型中，其半数有效剂量（ED50）分别为0.6和1 mg/kg。在完整大鼠中，单独给药时，它能剂量依赖性地抑制内源性雄激素对精囊（ED50约为1 mg/kg）和前列腺（ED50约为3 mg/kg）重量的影响。这些结果表明，这些新化合物可能作为雄激素受体的特异性标记物，以及用于治疗雄激素依赖性疾病或病症，如前列腺癌、痤疮、多毛症和男性型秃发。
