Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β

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• 作者：Filippo Minutolo ; Simone Bertini ; Carlotta Granchi ; Teresa Marchitiello ; Giovanni Prota ; Simona Rapposelli ; Tiziano Tuccinardi ; Adriano Martinelli ; Jillian R. Gunther ; Kathryn E. Carlson ; John A. Katz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：February 12, 2009
• 年：2009
• 卷：52
• 期：3
• 页码：858-867
• 全文大小：286K
• 年卷期：v.52,no.3(February 12, 2009)
• ISSN：1520-4804

文摘

The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERβ-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K_i = 7.1 nM) and selectivity for ERβ over ERα. Moreover, in transcription assays, it proved to be a selective and potent ERβ-full agonist with an EC₅₀ of 4.8 nM.