艾多昔芬
艾多昔芬 性质
| 熔点 | 108-109° (McCague et al.) |
|---|---|
| 沸点 | 573.4±50.0 °C(Predicted) |
| 密度 | 1.329 |
| 储存条件 | 2-8°C |
| 酸度系数(pKa) | 9.61±0.20(Predicted) |
| 形态 | 固体 |
| 颜色 | 白色至米白色 |
艾多昔芬 用途与合成方法
第一个上市的雌激素受体调节剂,礼莱的雷洛昔芬(ralox ifene)可广泛用于激素替代疗法的缓解,但用于控制骨质疏松效果不令人满意。SB公司认为,放弃艾多昔芬对骨质疏松的治疗研究原因在于经过1年来的Ⅲ 期临床试验的安全性评估,发现有妇科症状副作用,这些症状有子宫内膜增厚、骨盆腔腹垂和息肉。子宫内膜增厚表现在基底细胞层而不是腺细胞层。腺细胞层增厚多与子宫癌有关。1998年,诺沃-诺德大公司也是因为病人的子宫内膜增厚而放弃了雌激素受体调节剂左美洛昔芬(levormeloxifene)的Ⅲ期临床研究。尽管还未发现雷洛昔芬有子宫内膜增厚作用,但是,最近艾多昔芬的研究结果表明这一类药物可能具有对子宫内膜的作用。
以上信息是由Chemicalbook的东方编辑整理。（2016-02-01） 以苯乙酸为起始原料,经酰氯化、酰化、烃化制得中间体4，如下图所示：
以苯酚为起始原料,经溴化、O-烃化、N-烃化制得7，如下图所示：
由1-[2-(4-溴苯氧基)乙基]吡咯烷(2)与镁反应得相应的格氏试剂，再与关键中间体1-(4-碘苯基)-2-苯基-1-丁酮(1)进行格氏反应，水解得1-(4-碘苯基)-1-[4-[(2-吡咯烷基)乙氧基]苯基]-2-苯基-1-丁醇，脱水，纯化得艾多昔芬。该路线已申请了中国专利，并得到受理。如下图所示：
Idoxifene (CB7432) 是一种组织特异性的选择性雌激素受体调节剂 (SERM)。
Estrogen receptor
Idoxifene possesses the protective roles in vascular smooth muscle cells by its blunting the angiotensin II-induced production of reactive oxygen species (ROS). Idoxifene evidently suppresses HSC activation, inhibits culture-activated HSC proliferation in a dose-dependent manner, and induces culture-activated HSC apoptosis in a time-dependent manner. Idoxifene acts in bone as an estrogen agonist for osteoblasts, and shows negligible agonist activity in human endometrial cells. Idoxifene and E2 protect hepatocytes from inflammatory cell injury by inhibiting activation of the NF-κB proinflammatory transcription factor.
Animals receive daily intraperitoneal injections of Estradiol (0.5 mg/kg) and an oral gavage of Idoxifene (0.02, 0.1, and 0.5 mg/kg) for 3 days after Dimethylnitrosamine (DMN) treatment. The blood levels of LDH and Estradiol (E2) and histological grades (scores 0 to 5) of liver zone 3 necrosis are evaluated. Idoxifene at doses of over 0.1 mg/kg significantly reduces the hepatic levels of collagen and MDA in the DMN model in a dose-dependent manner. Although Idoxifene and E2 are administered by different routes, i.e., by oral ingestion and intraperitoneal injection, respectively, the antifibrotic effect of a dose of 0.5 mg/kg of Idoxifene is somewhat greater than that of the same dose of E2.
