Rew Yosup, McMinn Dustin L, Wang Zhulun, He Xiao, Hungate Randall W, Jaen Juan C, Sudom Athena, Sun Daqing, Tu Hua, Ursu Stefania, Villemure Elisia, Walker Nigel P C, Yan Xuelei, Ye Qiuping, Powers Jay P
Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2009 Mar 15;19(6):1797-801. doi: 10.1016/j.bmcl.2009.01.058. Epub 2009 Jan 23.
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
本文描述了哌啶基苯甲酰胺系列11β-羟基类固醇脱氢酶1（11β-HSD1）抑制剂的发现与优化。该系列源自环己基苯甲酰胺先导结构，以解决环己基苯甲酰胺结构所观察到的孕烷X受体（PXR）选择性、高非特异性蛋白结合、低溶解度、体内暴露有限以及体外细胞毒性等问题。这些努力导致了哌啶基苯甲酰胺15的发现，其性能优于环己基苯甲酰胺衍生物。
