钠-葡萄糖协同转运蛋白抑制剂的合成及降血糖活性  

Synthesis and anti-hyperglycemic activity of SGLT2 inhibitors

作　　者：史永恒[1,2] 赵桂龙[1] 刘巍[1] 邵华[1] 汤立达[3] 王玉丽[1] 徐为人[1,2] 

机构地区：[1]天津药物研究院天津市新药设计与发现重点实验室,天津300193 [2]天津医科大学药学院,天津300070 [3]天津药物研究院药代动力学与药效动力学省部共建国家重点实验室,天津300193

出　　处：《中国药物化学杂志》2011年第1期57-59,共3页Chinese Journal of Medicinal Chemistry

基　　金：天津市科技支撑计划重点项目(10ZCKFSH01300)

摘　　要：目的对钠-葡萄糖共转运子2(SGLT2)抑制剂dapagliflozin的两个苯环之间的亚甲基进行甲基化衍生,考察所得衍生物的降血糖活性。方法以5-溴-2-取代苯甲酸为起始物,经付克酰基化、格氏试剂的亲核加成、还原、溴-锂交换、偶合、还原、全乙酰化和脱乙酰化反应合成目标化合物。采用小鼠口服葡萄糖耐量试验测试目标化合物的降血糖活性。结果与结论合成了3个目标化合物,其结构经1H-NMR和ESI-MS谱确证。降血糖活性测试表明,阳性对照和目标化合物的血糖抑制率分别为79%(dapagliflozin)、38%(1a)、32%(1b)和43%(1c),3个目标化合物均具有较强的降血糖活性,但比阳性对照药dapagliflozin弱。Sodium-glucose cotransporter 2（SGLT2） inhibitors are a class of promising agents for the treatment of type 2 diabetes,among which dapagliflozin was the most advanced one.In order to investigate the effect of the attachment of one methyl group to the methylene between the two benzene rings of the dapagliflozin,three compounds were designed and synthesized.Starting from three 5-bromo-2-substitutedbenzoic acids,the target compounds were prepared through Friedel-Crafts acylation,nucleophilic addition by Grignard reagent,reduction,bromine-lithium exchange,nucleophilic addition,reduction,peracetylation and deacetylation.The target compounds were evaluated through mice oral glucose tolerance test（OGTT）,and the inhibition rates of glycemic level were 79%（dapagliflozin）,38%（1a）,32%（1b） and 43%（1c）,which indicated that although these three target compounds possess potent anti-hyperglycemic activities,they were all significantly less potent than the positive control dapagliflozin.

关 键 词：钠-葡萄糖共转运子2 合成 口服葡萄糖耐量试验(OGTT) 降血糖活性 

分 类 号：R914[医药卫生—药物化学]