Nonsteroidal Glucocorticoid Agonists: Tetrahydronaphthalenes with Alternative Steroidal A-Ring Mimetics Possessing Dissociated (Transrepression/Transactivation) Efficacy Selectivity

详细信息    查看全文

• 作者：Keith Biggadike ; Mohamed Boudjelal ; Margaret Clackers ; Diane M. Coe ; Derek A. Demaine ; George W. Hardy ; Davina Humphreys ; Graham G. A. Inglis ; Michael J. Johnston ; Haydn T. Jones ; David House ; Richard
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：December 27, 2007
• 年：2007
• 卷：50
• 期：26
• 页码：6519 - 6534
• 全文大小：939K
• 年卷期：v.50,no.26(December 27, 2007)
• ISSN：1520-4804

文摘

The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFκB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFκB agonism with pIC₅₀ of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFκB agonism with pIC₅₀ of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC₅₀ of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.