Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

详细信息    查看全文

• 作者：Simone Bertini ; Andrea De Cupertinis ; Carlotta Granchi ; Barbara Bargagli ; Tiziano Tuccinardi ; Adriano Martinelli ; Marco Macchia ; Jillian R. Gunther ; Kathryn E. Carlson ; John A. Katzenellenbogen ; Filippo Minutolo
• 关键词：Estrogen ; Receptor binding ; Agonists ; Salicylaldoxime ; Docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：46
• 期：6
• 页码：2453-2462
• 全文大小：1077 K

文摘

In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with K_i values reaching the sub-nanomolar range (K_i = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC₅₀ = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.