Dhar J D, Dwivedi A, Srivastava A, Setty B S
Division of Endocrinology, Central Drug Research Institute, Lucknow, India.
Contraception. 1994 Jun;49(6):609-16. doi: 10.1016/0010-7824(94)90102-3.
In an endeavour to develop potent anti-implantation agents, a new antiestrogen, CDRI 85/287 (2-(4-2-piperidinoethoxy)phenyl-3-phenyl(2H)benzo(b)pyran), virtually devoid of agonistic activity, was identified. The present study deals with anti-implantation and estrogen agonistic-antagonistic activities of four structural analogues of 85/287. Results show that none of the compounds induced vaginal cornification, even at doses as high as 2.5 mg/kg. Compounds having p-hydroxyphenyl group at position-3 or hydroxy group at position-7 showed better estrogen receptor affinity (6.6 and 25.3% E2) as well as antiestogenic activity. When 3-p-hydroxyphenyl was replaced by 3-p-methoxyphenyl, a marked reduction in the receptor affinity was observed. However, this compound was relatively more potent as an anti-implantation agent, possibly due to its conversion to hydroxylated metabolite in vivo. The provision of aminoethoxy side chain at para-position and a shift in the piperidinoethoxy side chain from position-4 to position-2 in these molecules resulted in a decrease in estrogenicity and increase in antagonistic property. Results are discussed with regard to molecular configuration, relative binding affinity of these compounds to their biological profile.
为了开发有效的抗着床药物，一种新的抗雌激素药物CDRI 85/287（2-(4-2-哌啶基乙氧基)苯基-3-苯基(2H)苯并(b)吡喃）被鉴定出来，该药物几乎没有激动活性。本研究探讨了85/287的四种结构类似物的抗着床和雌激素激动-拮抗活性。结果表明，即使剂量高达2.5mg/kg，这些化合物也均未诱导阴道角质化。在3位具有对羟基苯基或在7位具有羟基的化合物表现出更好的雌激素受体亲和力（分别为6.6%和25.3%的E2）以及抗雌激素活性。当3-对羟基苯基被3-对甲氧基苯基取代时，观察到受体亲和力显著降低。然而，该化合物作为抗着床药物相对更有效，这可能是由于其在体内转化为羟基化代谢产物。在这些分子的对位提供氨基乙氧基侧链以及将哌啶基乙氧基侧链从4位转移到2位导致雌激素活性降低和拮抗特性增加。针对这些化合物的分子构型、相对结合亲和力与其生物学特性的关系进行了讨论。
