PPARγ非激动配体:基于PPARγ部分激动剂的结构优化  

PPARγ non-agonist ligand: the structure optimization based on PPARγ partial agonist

作　　者：郑义[1] 环奕[2] 刘守信[1] 张莉婧[2] 王悦[2] 王星[2] 冯志强[2] 申竹芳[2] ZHENG Yi HUAN Yi LIU Shou-xin ZHANG Li-jing WANG Yue WANG Xing FENG Zhi-qiang SHEN Zhu-fang(Hebei University of Science and Technology, Shijiazhuang 050018, China Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China)

机构地区：[1]河北科技大学,河北石家庄050018 [2]中国医学科学院北京协和医学院药物研究所,北京100050

出　　处：《药学学报》2017年第9期1424-1431,共8页Acta Pharmaceutica Sinica

摘　　要：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 indicate that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγ Ser273 phosphorylation mediated by cyclin-dependent kinase 5（Cdk5）, which is resulted from the binding activity for PPARγ. While, the side effects of TZDs may be related to the agonistic potency for PPARγ. In this article, 15 target compounds were designed and synthesized based on the structure of PPARγ partial agonist INT131, with the aim of maintaining the insulin-sensitizing activity and reducing the side effects of INT131. The structures of these compounds were confirmed by 1H NMR and ESI-MS, and their binding activities and agonistic potencies for PPARγ were measured. The binding activity of compound 15 is 88.47% of rosiglitazone, which is similar to INT131（98.55%）, but the agonistic potency of compound 15 is 1.41% of rosiglitazone, obviously lower than INT131（15.18%）.

关 键 词：胰岛素增敏剂 PPARγ非激动配体 PPARγ部分激动剂 2型糖尿病 

分 类 号：R916[医药卫生—药学]