Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists

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• 作者：Stephen D. Lotesta ; ^{slotesta@vitaerx.com" class="auth_mail" title="E-mail the corresponding author} ; Andrew P. Marcus ; Yajun Zheng ; Katerina Leftheris ; Paul B. Noto ; Shi Meng ; Geeta Kandpal ; Guozhou Chen ; Jing Zhou ; Brian McKeever ; Yuri Bukhtiyarov ; Yi Zhao ; Deepak S. Lala ; Suresh B. Singh ; Gerard M. McGeehan
• 关键词：Mineralocorticoid receptor ; MR ; MR antagonist ; Spirooxindole ; Dibenzoxazepine
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：24
• 期：6
• 页码：1384-1391
• 全文大小：1920 K

文摘

Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.