Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1

被引：11

作者：

Tice, Colin M. ^{[1
]}

Zhao, Wei ^{[1
]}

Krosky, Paula M. ^{[1
]}

Kruk, Barbara A. ^{[1
]}

Berbaum, Jennifer ^{[1
]}

Johnson, Judith A. ^{[1
]}

Bukhtiyarov, Yuri ^{[1
]}

Panemangalore, Reshma ^{[1
]}

Scott, Boyd B. ^{[1
]}

Zhao, Yi ^{[1
]}

Bruno, Joseph G. ^{[1
]}

Howard, Lamont ^{[1
]}

Togias, Jennifer ^{[1
]}

Ye, Yuan-Jie ^{[1
]}

Singh, Suresh B. ^{[1
]}

McKeever, Brian M. ^{[1
]}

Lindblom, Peter R. ^{[1
]}

Guo, Joan ^{[1
]}

Guo, Rong ^{[1
]}

Nar, Herbert ^{[2
]}

Schuler-Metz, Annette ^{[2
]}

Gregg, Richard E. ^{[1
]}

Leftheris, Katerina ^{[1
]}

Harrison, Richard K. ^{[1
]}

McGeehan, Gerard M. ^{[1
]}

Zhuang, Linghang ^{[1
]}

Claremon, David A. ^{[1
]}

机构：

[1] Vitae Pharmaceut, Ft Washington, PA 19034 USA

[2] Boehringer Ingelheim Pharma GmbH & Co KG, D-88400 Biberach, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 22期

关键词：

11 beta-Hydroxysteroid dehydrogenase; Diabetes; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; METABOLIC SYNDROME; GLUCOCORTICOID ACTION; VISCERAL OBESITY; MICE; DISEASE; POTENT; MODEL;

D O I：

10.1016/j.bmcl.2010.08.142

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC50 of 15.2 nM against human 11 beta-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat. (C) 2010 Elsevier Ltd. All rights reserved.

引用

收藏

页码：6725 / 6729

页数：5

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