Johnston J O
Merrell Dow Research Institute, Cincinnati, OH 45215.
Steroids. 1987 Jul-Sep;50(1-3):105-20. doi: 10.1016/0039-128x(83)90065-x.
MDL 18,962 was shown to be a highly specific, potent (Ki = 3-4 nM), enzyme-activated inhibitor of aromatase with minimal intrinsic endocrine properties. The affinity of MDL 18,962 was higher for human and baboon placental aromatase than for rhesus placental or rodent ovarian aromatase. These species differences necessitated the development of a novel model of peripheral aromatase utilizing human enzyme. Human choriocarcinoma trophoblast xenografts in athymic nude mice were used for pharmacologic and pharmacokinetic evaluation of MDL 18,962. The ED50 for inhibition of aromatase activity in these trophoblast tumors at 6 h post-treatment was 1.4 mg/kg, s.c. and 3.0 mg/kg, oral. Preliminary results indicated that the ED50 for inhibition of peripheral aromatization of androgen by MDL 18,962 in female baboons was 0.01 mg/kg, i.v. and 4 mg/kg, oral.
MDL 18,962被证明是一种高度特异性、强效（Ki = 3 - 4 nM）的芳香化酶酶激活抑制剂，其内在内分泌特性极小。MDL 18,962对人和狒狒胎盘芳香化酶的亲和力高于恒河猴胎盘或啮齿动物卵巢芳香化酶。这些物种差异使得利用人源酶开发一种新型外周芳香化酶模型成为必要。无胸腺裸鼠中的人绒毛膜癌滋养层异种移植物被用于MDL 18,962的药理学和药代动力学评估。治疗后6小时，这些滋养层肿瘤中抑制芳香化酶活性的ED50为皮下注射1.4 mg/kg和口服3.0 mg/kg。初步结果表明，MDL 18,962在雌性狒狒中抑制雄激素外周芳香化的ED50为静脉注射0.01 mg/kg和口服4 mg/kg。
