发现新型双功能药物作为过氧化物酶体增殖物激活受体γ（PPARγ）激动剂和11β-羟类固醇脱氢酶1（11β-HSD1）抑制剂用于治疗糖尿病。
Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes.
作者信息
Ye Yang-liang, Zhou Zhou, Zou Han-jun, Shen Yu, Xu Ti-Fei, Tang Jing, Yin Hua-zhong, Chen Min-li, Leng Ying, Shen Jian-hua
机构信息
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
出版信息
Bioorg Med Chem. 2009 Aug 1;17(15):5722-32. doi: 10.1016/j.bmc.2009.05.082. Epub 2009 Jun 12.
PPARgamma and 11beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARgamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPARgamma and inhibit 11beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARgamma (EC(50)=6.76 microM) and 11beta-HSD1 (IC(50)=0.76 microM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
过氧化物酶体增殖物激活受体γ（PPARγ）和11β-羟基类固醇脱氢酶1（11β-HSD1）是2型糖尿病颇具吸引力的治疗靶点。然而，PPARγ激动剂会诱导脂肪生成，从而导致体重增加的副作用，而11β-HSD1抑制剂可阻止脂肪生成，可能对糖尿病患者肥胖症的治疗有益。我们首次设计并合成了一系列α-芳氧基-α-甲基氢化肉桂酸作为双功能药物，它们可同时激活PPARγ并抑制11β-HSD1。与先导化合物2相比，化合物11e表现出最强的抑制活性，其体外PPARγ（半数有效浓度[EC(50)] = 6.76微摩尔）和11β-HSD1（半数抑制浓度[IC(50)] = 0.76微摩尔）。还展示了对化合物11e的分子模拟研究。在成熟的糖尿病和肥胖小鼠及大鼠模型中，化合物11e在降低血糖、甘油三酯和体脂方面显示出优异疗效，并且具有良好的药物代谢动力学性质。
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