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

Authors :
Tice CM
Zhao W
Krosky PM
Kruk BA
Berbaum J
Johnson JA
Bukhtiyarov Y
Panemangalore R
Scott BB
Zhao Y
Bruno JG
Howard L
Togias J
Ye YJ
Singh SB
McKeever BM
Lindblom PR
Guo J
Guo R
Nar H
Schuler-Metz A
Gregg RE
Leftheris K
Harrison RK
McGeehan GM
Zhuang L
Claremon DA
Source :
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Nov 15; Vol. 20 (22), pp. 6725-9. Date of Electronic Publication: 2010 Sep 07.
Publication Year :
2010

Abstract

Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM 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.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3405
Volume :
20
Issue :
22
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
20864344
Full Text :
https://doi.org/10.1016/j.bmcl.2010.08.142