药学学报, 2016, 51(6): 947-953
引用本文:
李艳萍, 易红, 姜心贝, 李卓荣. 黄嘌呤类DPP-IV抑制剂的化学合成和生物活性研究[J]. 药学学报, 2016, 51(6): 947-953.
LI Yan-ping, YI Hong, JIANG Xin-bei, LI Zhuo-rong. Synthesis and biological activity of substituted xanthines as DPP-IV inhibitors[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 947-953.

黄嘌呤类DPP-IV抑制剂的化学合成和生物活性研究
李艳萍, 易红, 姜心贝, 李卓荣
中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
摘要:
为了考察降血糖药物利拉利汀(linagliptin, LNP)的黄嘌呤结构母核上N-1、N-7和C-8取代基对DPP-IV酶抑制活性的贡献,并且希望找到活性更强的新DPP-IV抑制剂,本研究以3-甲基-8-溴黄嘌呤为原料,通过引入不同取代基,设计合成一系列LNP的类似物,并测定这些化合物对DPP-IV酶的抑制率。活性测定结果显示,这类化合物在50 nmol·L-1浓度下大多具有明显的DPP-IV酶抑制活性,其中1a1d1f对DPP-IV酶的抑制率大于50%。本研究初步探索了黄嘌呤类化合物对DPP-IV酶抑制活性的构效关系,为以后的研究提供了新的思路和借鉴。
关键词:    二肽基肽酶-4 抑制剂      利拉利汀      合成      构效关系     
Synthesis and biological activity of substituted xanthines as DPP-IV inhibitors
LI Yan-ping, YI Hong, JIANG Xin-bei, LI Zhuo-rong
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
In order to find more potential DPP-IV inhibitor, a series of xanthine-scaffold analogs of linagliptin, an approved antidiabetes drug, were designed and synthesized for SAR study. All compounds with a concentration of 50 nmol·L-1 showed the inhibitory activity against DPP-IV enzyme in vitro, and the inhibition rate of compounds 1a, 1d and 1f was over 50%. Virtual docking was also performed to facilitate the SAR analysis of these substituted xanthines.
Key words:    dipeptidyl peptidase IV inhibitor    linagliptin    synthesis    SAR   
收稿日期: 2015-12-22
DOI: 10.16438/j.0513-4870.2015-1171
基金项目: 北京市自然科学基金资助项目(7132166).
通讯作者: 李卓荣,Tel/Fax:86-10-63027185,E-mail:l-z-r@263.net
Email: l-z-r@263.net
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