Journal of Medicinal Chemistry p. 6050 - 6062 (2011)
Update date:2022-08-03
Topics:
Xu, Zhenrong
Tice, Colin M.
Zhao, Wei
Cacatian, Salvacion
Ye, Yuan-Jie
Singh, Suresh B.
Lindblom, Peter
McKeever, Brian M.
Krosky, Paula M.
Kruk, Barbara A.
Berbaum, Jennifer
Harrison, Richard K.
Johnson, Judith A.
Bukhtiyarov, Yuri
Panemangalore, Reshma
Scott, Boyd B.
Zhao, Yi
Bruno, Joseph G.
Togias, Jennifer
Guo, Joan
Guo, Rong
Carroll, Patrick J.
McGeehan, Gerard M.
Zhuang, Linghang
He, Wei
Claremon, David A.
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC50 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.
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