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

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC50 of 15.2nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% or...

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Published in:Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (22), p.6725-6729
Main Authors: Tice, Colin M., Zhao, Wei, Krosky, Paula M., Kruk, Barbara A., Berbaum, Jennifer, Johnson, Judith A., Bukhtiyarov, Yuri, Panemangalore, Reshma, Scott, Boyd B., Zhao, Yi, Bruno, Joseph G., Howard, Lamont, Togias, Jennifer, Ye, Yuan-Jie, Singh, Suresh B., McKeever, Brian M., Lindblom, Peter R., Guo, Joan, Guo, Rong, Nar, Herbert, Schuler-Metz, Annette, Gregg, Richard E., Leftheris, Katerina, Harrison, Richard K., McGeehan, Gerard M., Zhuang, Linghang, Claremon, David A.
Format: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenase Type 1 - antagonists & inhibitors
11β-Hydroxysteroid dehydrogenase
Adamantane - chemistry
Adamantane - pharmacology
Animals
Biological and medical sciences
Diabetes
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General and cellular metabolism. Vitamins
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Rats
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Summary:Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC50 of 15.2nM against human 11β-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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.08.142