甘氨酰胺类dpp-iv抑制剂的设计合成及体外活性研究.docVIP

甘氨酰胺类DPP-IV抑制剂的设计、合成及体外活性研究 韩 蓓, 环 奕, 林紫云, 李 鹏, 申竹芳, 尹大力, 黄海洪* (中国医学科学院、北京协和医学院药物研究所, 北京 ) 摘要: 以P32/98和化合物A为先导化合物, 对其进行结构改造。在羧基端引入含氮杂环形成酰胺, 在羰基α-位引入不同取代基, 设计合成了19个以甘氨酰胺为基本骨架的二肽基肽酶IV (dipeptidyl peptidase, DPP-IV) 抑制剂。利用1H NMR和HRMS确证了它们的结构, 并对其进行酶水平的体外药理活性筛选, 测试了它们对DPP-IV的抑制作用, 获得了初步的构效关系结果。 : 二肽基肽酶A 文章编号: 0513-4870 (2010) 11-1379-06 Design, synthesis and in vitro activity of glycinamide-bearing compounds as DPP-IV inhibitors HAN Bei, HUAN Yi, LIN Zi-yun, LI Peng, SHEN Zhu-fang, YIN Da-li, HUANG Hai-hong* (Institute of Materia Medica, Peking Union Medical College Chinese Academy of Medical Sciences, Beijing 100050, China) Abstract: To research the structure-activity relationship (SAR) of glycinamide-bearing compounds that used as inhibitors of dipeptidyl peptidase IV (DPP-IV), P32/98 and compound A were chosen as the leading compounds, heterocycles containing nitrogen atom were introduced to form amide, and different residues on α-position of carbonyl were designed. The nineteen designed compounds were synthesized by a simple route and were evaluated as inhibitors of DPP-IV. All of the structures were characterized by 1H NMR and HRMS. The preliminary SAR result was obtained. Key words: dipeptidyl peptidase IV inhibitor; synthesis; glycinamide; structure-activity relationship (2型糖尿病 (type 2 diabetes mellitus, T2DM) 是一类常见的慢性综合性疾病, 占糖尿病患者总数的90% 以上。目前临床上使用的抗糖尿病药物主要有胰岛素、磺酰脲类、α-葡萄糖苷酶抑制剂、双胍类和噻唑烷二酮类胰岛素增敏剂等, 这些药物在临床应用时均有不足之处, 如存在肝毒性等副作用。因此, 基于T2DM的致病原因, 许多新的药物靶点最近已被开发。其中, 以DPP-IV为靶点的药物研究最为突出[1]。DPP-IV抑制剂能够增强胰高血糖素样肽1的片 (glucagon-like peptide I, GLP-1) 和抑胃肽 (glucose-dependent insulinotropic polypeptide, GIP) 的活性, 并能提高葡萄糖耐受水平[2]。近年来研发的DPP-IV抑制剂在降低血糖的同时具有保护β细胞功能的作用, 已成为T2DM治疗药物的研发热点之一。 目前在研的或已上市的DPP-IV抑制剂的结构变化多样, 其中以α-氨基酸系列化合物的研究最为广泛深入, 主要包括硼酸衍生物、二肽二苯基磷酸酯衍生物、邻苯二甲酰亚胺衍生物、异喹啉衍生物及甘氨酰基吡咯烷噻唑烷衍生物等[3]。在图1所示的结构 中, 上市药物ildagliptin (LAF-237)[4]和axagliptin (BMS-477118)[5