Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor

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• 作者：Zhuang Jin^a ; Hua Lin^a ; Sathish Srinivasan^b ; Jerome C. Nwachukwu^b ; Nelson Bruno^b ; Patrick R. Griffin^a ; Kendall W. Nettles^b ; ; Theodore M. Kamenecka^a ; ^{kameneck@scripps.edu}
• 关键词：AF-1 ; activation function-1 ; AF-2 ; activation function-2 ; AP-1 ; activator protein 1 ; dppp ; 1 ; 3-bis(diphenylphosphino)propane ; DEX ; dexamethasone ; DIEA ; N ; N-diisopropylethylamine ; FKBP5 ; FK506-binding protein 5 ; GR ; glucocorticoid receptor ; GRE ; glucocorticoid-response element ; HATU ; 1-[bis(dimethylamino)methylene]-1H-1 ; 2 ; 3-triazolo[4 ; 5-b]pyridinium 3-oxid hexafluorophosphate ; IL-6 ; Interleukin-6 ; LBD ; ligand-binding domain ; LPS ; lipopolysaccharide ; MMTV ; mouse mammary tumor virus ; NF-κB ; nuclear
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：27
• 期：2
• 页码：347-353
• 全文大小：2024 K
• 卷排序：27

文摘

Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.