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最近研究表明,TZD类药物的胰岛素增敏作用是基于其对Cdk5介导的PPARγSer273的磷酸化的抑制,起因于其对PPARγ的结合活性;而TZD类药物的不良反应是起因于其对PPARγ的激动活性。本文以PPARγ部分激动剂INT131分子结构为模板,以保持其结合活性、降低或消除其激动活性为目标,设计合成了15个新化合物,其结构通过1H NMR和ESI-MS确证。初步药理活性筛选显示,化合物15的PPARγ结合活性为罗格列酮的88.47%,与INT131(98.55%)相近;而其激动活性仅为罗格列酮的1.41%,明显优于INT131(15.18%)。
Recent studies have shown that the insulin sensitizing effect of TZD-based drugs is based on their inhibition of Cdk5-mediated phosphorylation of PPARγSer273 due to its binding activity to PPARγ, whereas adverse effects of TZD-drugs are due to its effect on PPARγ Agonistic activity. In this paper, 15 new compounds were designed and synthesized based on the molecular structure of PPARγ partial agonist INT131 in order to maintain its binding activity and reduce or eliminate its agonistic activity. The structure was confirmed by 1H NMR and ESI-MS. Preliminary pharmacological activity screening showed that PPARγ binding activity of Compound 15 was 88.47% of that of rosiglitazone, which was similar to that of INT131 (98.55%), whereas its activity was only 1.41% of that of rosiglitazone, significantly higher than that of INT131 (15.18% ).