黄嘌呤类DPP-Ⅳ抑制剂的化学合成和生物活性研究

Synthesis and biological activity of substituted xanthines as DPP-Ⅳ inhibitors

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1a、1d和1f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。

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.