Sharma A P, Saeed A, Durani S, Kapil R S
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India.
J Med Chem. 1990 Dec;33(12):3222-9. doi: 10.1021/jm00174a020.
Phenolic analogues of 2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (1), a novel antiestrogen, were synthesized and evaluated for their structure-activity relationship. Incorporation of OH at position 7 was found to improve receptor affinity of the benzopyran while having no effect on its action as an antagonist. Similar substitution of 2-phenyl as well potentiated receptor affinity as well as antagonist activity of the prototype. The monophenol 19 and the diphenol 25 were thus found to be good receptor ligands, devoid of estrogen agonist activity and associated with marked antiestrogenic activity of comparable order. Both caused nearly complete inhibition of the estradiol stimulated uterine growth in rats as well as mice and were thus found to be better antiestrogens than tamoxifen, trioxifen, and LY-117018. A binding-site model for estrogen receptor rationalizing the structure-activity relationship of benzopyrans in relation to that of the triarylethylene and the triarylpropenone antiestrogens has been discussed.
新型抗雌激素药物2-[4-(2-哌啶基乙氧基)苯基]-3-苯基-2H-1-苯并吡喃（1）的酚类类似物被合成，并对其构效关系进行了评估。发现在7位引入羟基可提高苯并吡喃的受体亲和力，而对其作为拮抗剂的作用没有影响。2-苯基的类似取代也增强了原型的受体亲和力和拮抗剂活性。因此，发现单酚19和双酚25是良好的受体配体，没有雌激素激动剂活性，且具有相当程度的显著抗雌激素活性。两者都几乎完全抑制了雌二醇刺激的大鼠和小鼠子宫生长，因此被发现是比他莫昔芬、三苯氧胺和LY-117018更好的抗雌激素药物。本文讨论了一个雌激素受体结合位点模型，该模型解释了苯并吡喃与三芳基乙烯和三芳基丙烯酮抗雌激素药物构效关系的合理性。
