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

详细信息    查看全文

• 作者：Nareshkumar Jain ; Jiayi Xu ; Ramesh M. Kanojia ; Fuyong Du ; Guo Jian-Zhong ; Emmanuel Pacia ; Muh-Tsann Lai ; Amy Musto ; George Allan ; Michael Reuman ; Xun Li ; DoWon Hahn ; Martin Cousineau ; Sean Peng ; David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 10, 2009
• 年：2009
• 卷：52
• 期：23
• 页码：7544-7569
• 全文大小：1673K
• 年卷期：v.52,no.23(December 10, 2009)
• ISSN：1520-4804

文摘

As part of a 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 as 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 the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as 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).