EXEMESTANE (FCE-24304), A NEW STEROIDAL AROMATASE INHIBITOR
EXEMESTANE (FCE-24304), A NEW STEROIDAL AROMATASE INHIBITOR
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DOI：
10.1016/0960-0760(92)90198-r
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发表时间：
1992-09-01
影响因子：
4.1
通讯作者：
COOMBES, RC
中科院分区：
文献类型：
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作者：
DISALLE, E;ORNATI, G;COOMBES, RC
依西美坦（FCE 24304; 6-亚甲基雄甾-1，4-二烯-3，17-二酮）是一种新型的口服不可逆芳香化酶抑制剂。其体外和体内药理学特性已与4-羟基雄烯二酮（4-OHA）进行了比较。在人胎盘芳香化酶的预孵育研究中，与4-OHA一样，西美坦显示出酶灭活特性，具有相似的亲和力（K（i）26 vs 29 nM）和较低的灭活速率（t1/2 13.9 vs 2.1 min）。相反，当在妊娠期血清促性腺激素处理的大鼠中进行测试时，在皮下给药（ED 50 1.8 vs 3.1 mg/kg）和经口给药（ED 50 3.7 vs > 100 mg/kg）后，西美坦在降低微粒体卵巢芳香酶活性方面比4-OHA更有效。没有发现阿司美坦对碳链酶或5-α-还原酶活性的干扰。该化合物对甾体受体没有任何相关的结合亲和力，但对雄激素受体有轻微的结合（几乎等于0.2%的二氢睾酮），如4-OHA。在第一个I期试验中，健康的绝经后志愿者被给予单次口服剂量的依西美坦，范围为0.5至800 mg，测定血浆雌酮（E1）、雌二醇（E2）和硫酸雌酮（E1 S）和尿雌激素（E1和E2），直至5-8天。降低雌激素的最小有效剂量为5 mg。在25 mg时，在第3天观察到最大抑制：血浆雌激素降至基础值的35（E1）、39（E2）和28%（E1 S），尿雌激素降至基础值的20（E1）和25%（E2），这些效应在第5天仍持续存在。在最高试验剂量800 mg维司坦下，未观察到对皮质醇、醛固酮、17-羟孕酮、DHEAS、LH和FSH血浆水平的影响，也未观察到显著不良事件。
Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (K(i) 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonodatropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs > 100 mg/kg). No interference of exemestane on desmolase or 5-alpha -reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (almost-equal-to 0.2% of dihydrotestosterone), like 4-OHA.In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.