Raloxifene agonism of estrogen receptor (ER) in post-menopausal endometrium is not negligible. Based on a rational drug design workflow, we synthesized 14 analogues of raloxifene bearing a polar group in the aromatic ring of the basic side chain (BSC) and/or changes in the bulkiness of the BSC amino group. Analogues with a polar BSC aromatic ring and amino group substituents of increasing volume displayed increasing ER antagonism in Ishikawa cells. Analogues with cyclohexylaminoethoxy (13a) or adamantylaminoethoxy BSC (13b) lacking a polar aromatic ring displayed high ER-binding affinity and ER antagonism in Ishikawa cells higher than raloxifene and similar to fulvestrant (ICI182,780). The endometrial surface epithelium of immature female CD1 mice injected with 13b was comparable to that of vehicle-treated mice, while that of mice treated with estradiol, raloxifene or 13b in combination with estradiol was hyperplastic. These findings indicate that raloxifene analogues with a bulky BSC amino group could provide for higher endometrial safety treatment of the menopausal syndrome.

绝经后子宫内膜中雌激素受体 (ER) 的雷洛昔芬激动作用不容忽视。基于合理的药物设计工作流程，我们合成了 14 种雷洛昔芬类似物，其在基本侧链 (BSC) 的芳环中带有一个极性基团和/或 BSC 氨基的体积变化。在石川细胞中，具有极性 BSC 芳环和氨基取代基的类似物显示出增加的 ER 拮抗作用。环己基氨基乙氧基( 13a)或金刚烷基氨基乙氧基BSC ( 13b ) 缺乏极性芳香环的类似物在 Ishikawa 细胞中显示出高 ER 结合亲和力和 ER 拮抗作用，高于雷洛昔芬，类似于氟维司群 (ICI182,780)。注射13b的未成熟雌性CD1小鼠子宫内膜表面上皮与载体治疗的小鼠相当，而用雌二醇、雷洛昔芬或13b与雌二醇联合治疗的小鼠则增生。这些发现表明，具有庞大 BSC 氨基的雷洛昔芬类似物可以为更年期综合征提供更高的子宫内膜安全性治疗。