基于结构的 11β-羟甾脱氢酶 1 型抑制剂 1,3-恶唑烷-2-酮的设计与合成。
Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1.
机构信息
Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Pennsylvania 19034, USA.
出版信息
J Med Chem. 2011 Sep 8;54(17):6050-62. doi: 10.1021/jm2005354. Epub 2011 Aug 4.
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.
基于结构的设计直接导致了 1,3-恶唑烷-2-酮 9a 的产生，其对 11β-HSD1 的体外抑制常数（IC(50)）为 42 nM。对 9a 进行优化以提高体外酶和细胞效力，得到了 25f，其对酶的 IC(50)值为 0.8 nM，在脂肪细胞中为 2.5 nM。此外，25f 在大鼠中的口服生物利用度为 94%，对 11β-HSD2 的选择性超过 1000 倍。在小鼠中，25f 分布到靶组织肝脏和脂肪组织，在食蟹猴中，口服 10 mg/kg 剂量可在皮质酮挑战后将皮质醇生成减少 85%。
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