Identification and Structure-Activity Relationships of Chromene-Derived Selective Estrogen Receptor Modulators for Treatment of Postmenopausal Symptoms

被引：98

作者：

Jain, Nareshkumar ^{[1
]}

Xu, Jiayi ^{[1
]}

Kanojia, Ramesh M. ^{[1
]}

Du, Fuyong ^{[1
]}

Guo Jian-Zhong ^{[1
]}

Pacia, Emmanuel ^{[1
]}

Lai, Muh-Tsann ^{[1
]}

Musto, Amy ^{[1
]}

Allan, George ^{[1
]}

Reuman, Michael ^{[1
]}

Li, Xun ^{[1
]}

Hahn, DoWon ^{[1
]}

Cousineau, Martin ^{[1
]}

Peng, Sean ^{[1
]}

Ritchie, David ^{[1
]}

Russell, Ronald ^{[1
]}

Lundeen, Scott ^{[1
]}

Sui, Zhihua ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Exton, PA 19341 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 23期

关键词：

CORONARY-HEART-DISEASE; TETRACYCLIC HETEROCOMPOUNDS; IN-VITRO; MULTIFUNCTIONAL MEDICINES; ANTIESTROGENIC ACTIVITY; RALOXIFENE ANALOG; GENE-EXPRESSION; PLUS PROGESTIN; HOT FLASHES; RAT MODEL;

D O I：

10.1021/jm900146e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

As part of it program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line its well in Ishikawa cell line with IC50 values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and file SERM raloxifene, 7-(R) wits found to be it potent SERM that behaved its antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were Significantly improved compared to those of the phase 2 development compound 9-(R).

引用

页码：7544 / 7569

页数：26

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