Johnston J O, Wright C L, Metcalf B W
Endocrinology. 1984 Aug;115(2):776-85. doi: 10.1210/endo-115-2-776.
The conversion of androgens to estrogens by aromatase represents a major alteration in hormonal expression, and its regulation offers a promising method for therapeutic control of disease processes that are hormonally dependent. The design of suicide inhibitors based on enzyme-activated mechanisms provides an attractive approach for regulation of estrogen biosynthesis. MDL 18,962, (10-2(-propynyl)estr-4-ene-3,17-dione), a C-10 substituted analog of the natural substrate androstenedione, was evaluated as a suicide inhibitor of aromatase. Appropriate kinetic evaluations of MLD 18,962 established it to be a highly potent [inhibition constant (Ki) = 4.5 +/- 1.3 nM] irreversible inhibitor of human placental aromatase. The 2-propynyl group was necessary for time-dependent inactivation, as this activity was lost in related compounds. The inactivation process was specific for aromatase, since other P450 enzyme systems are not inactivated by MDL 18,962. This compound exhibited minimal intrinsic hormonal properties, since weak binding affinities were observed for cytosolic androgen, estrogen, or progestin receptors. The stimulation of ovarian aromatase activity by gonadotropins in immature mice was inhibited in animals implanted with 10-mm MDL 18,962 Silastic implants. This inhibition of estrogen biosynthesis suppressed estrogen-dependent uterine growth in these mice.
芳香化酶将雄激素转化为雌激素代表了激素表达的一种主要改变，其调节为激素依赖性疾病过程的治疗控制提供了一种有前景的方法。基于酶激活机制设计自杀性抑制剂为调节雌激素生物合成提供了一种有吸引力的方法。MDL 18,962，即(10-2(-丙炔基)雌-4-烯-3,17-二酮)，作为天然底物雄烯二酮的C-10取代类似物，被评估为芳香化酶的自杀性抑制剂。对MDL 18,962进行适当的动力学评估确定它是一种高效的[抑制常数(Ki)=4.5±1.3 nM]人胎盘芳香化酶不可逆抑制剂。2-丙炔基对于时间依赖性失活是必需的，因为相关化合物中这种活性丧失了。失活过程对芳香化酶具有特异性，因为其他P450酶系统不会被MDL 18,962失活。该化合物表现出最小的内在激素特性，因为对胞质雄激素、雌激素或孕激素受体的结合亲和力较弱。在植入10-mm MDL 18,962硅橡胶植入物的未成熟小鼠中，促性腺激素对卵巢芳香化酶活性的刺激受到抑制。雌激素生物合成的这种抑制抑制了这些小鼠中雌激素依赖性的子宫生长。
