Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists
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- 作者：James E. Sheppeck II ; John L. Gilmore ; Hai-Yun Xiao ; T.G. Murali Dhar ; David Nirschl ; Arthur M. Doweyko ; Jack S. Sack ; Martin J. Corbett ; Mary F. Malley ; Jack Z. Gougoutas ; Lorraine Mckay ; Mark D. Cunningham ; Sium F. Habte ; John H. Dodd ; Steven G. Nadler ; John E. Somerville ; Joel C. Barrish
- 关键词：GR agonist ; Glucocortocoid receptor ; Dissociated GR inhibitors
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 October, 2013
- 年：2013
- 卷：23
- 期：19
- 页码：5442-5447
- 全文大小：1018 K
文摘
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.