Discovery of adamantane ethers as inhibitors of 11β-HSD-1: Synthesis and biological evaluation

The synthesis and SAR of adamantane ethers are described as novel, potent and selective inhibitors of 11β-HSD-1. An X-ray crystal structure of one of these inhibitors bound to h-11β-HSD-1 is also described. A novel class of adamantane ethers 11β-hydroxysteroid hydrogenase type I inhibitors has been...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (3), p.750-755
Main Authors: Patel, Jyoti R., Shuai, Qi, Dinges, Jurgen, Winn, Marty, Pliushchev, Marina, Fung, Steven, Monzon, Katina, Chiou, William, Wang, Jiahong, Pan, Liping, Wagaw, Seble, Engstrom, Kenneth, Kerdesky, Francis A., Longenecker, Kenton, Judge, Russell, Qin, Wenying, Imade, Hovis M., Stolarik, DeAnne, Beno, David W.A., Brune, Michael, Chovan, Linda E., Sham, Hing L., Jacobson, Peer, Link, J.T.
Format: Article
Language:English
Subjects:
11β-HSD-1
11β-HSD-2
Adamantane ethers
Biological and medical sciences
Inhibitor
Medical sciences
Metabolic syndrome
Miscellaneous
Pharmacology. Drug treatments
X-ray crystal structure
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Summary:The synthesis and SAR of adamantane ethers are described as novel, potent and selective inhibitors of 11β-HSD-1. An X-ray crystal structure of one of these inhibitors bound to h-11β-HSD-1 is also described. A novel class of adamantane ethers 11β-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure–activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.10.074