| Literature DB >> 21786805 |
Zhenrong Xu1, Colin M Tice, Wei Zhao, Salvacion Cacatian, Yuan-Jie Ye, Suresh B Singh, Peter Lindblom, Brian M McKeever, Paula M Krosky, Barbara A Kruk, Jennifer Berbaum, Richard K Harrison, Judith A Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Boyd B Scott, Yi Zhao, Joseph G Bruno, Jennifer Togias, Joan Guo, Rong Guo, Patrick J Carroll, Gerard M McGeehan, Linghang Zhuang, Wei He, David A Claremon.
Abstract
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.Entities:
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Year: 2011 PMID： 21786805 DOI： 10.1021/jm2005354
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446