Structure-Based Design and Synthesis of 1,3-Oxazinan-2-one Inhibitors of 11尾-Hydroxysteroid Dehydrogenase Type 1
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- 作者：Zhenrong Xu ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：September 8, 2011
- 年：2011
- 卷：54
- 期：17
- 页码：6050-6062
- 全文大小：1124K
- 年卷期：v.54,no.17(September 8, 2011)
- ISSN：1520-4804
文摘
Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC50 of 42 nM against 11尾-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC50 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脳 selectivity over 11尾-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.