Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration

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• 作者：Ralph P. Robinson* ; Leonard Buckbinder ; Amber I. Haugeto ; Patricia A. McNiff ; Michele L. Millham ; Matthew R. Reese ; Jean F. Schaefer ; Yuriy A. Abramov ; Jon Bordner ; Yves A. Chantigny ; Edward F. Kleinm
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：March 26, 2009
• 年：2009
• 卷：52
• 期：6
• 页码：1731-1743
• 全文大小：273K
• 年卷期：v.52,no.6(March 26, 2009)
• ISSN：1520-4804

文摘

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or “dissociated” agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.