四氢异喹啉类PCSK9变构抑制剂的合成  

Synthesis of Tetrahydroisoquinoline PCSK9 Allosteric Inhibitors

作　　者：李文雅 刘洪涛 马志欣 李文燕[1] LI Wenya;LIU Hongtao;MA Zhixin;LI Wenyan(College of Chemistry and Materials Science,Hebei Normal University,Hebei Key Laboratory of Organic Functional Molecules,Hebei Shijiazhuang 050024,China;Department of Pharmacy,The First Hospital of Hebei Medical University,Hebei Shijiazhuang 050000,China)

机构地区：[1]河北师范大学化学与材料科学学院,河北省有机功能分子重点实验室,河北石家庄050024 [2]河北医科大学第一医院药剂科,河北石家庄050000

出　　处：《河北师范大学学报（自然科学版）》2023年第6期598-601,共4页Journal of Hebei Normal University：Natural Science

基　　金：河北省自然科学基金京津冀基础研究合作专项(H2019205318,19JCZDJC63900);河北省自然科学基金生物医药联合基金培育项目(H2022307031)。

摘　　要：PCSK9是经过临床验证的有效治疗高胆固醇血症的靶点,抑制其活性可明显降低血浆胆固醇水平,延缓动脉粥样硬化进程.四氢异喹啉类化合物1是一种PCSK9变构抑制剂,结构新颖、作用机制独特.以2-氨基噻唑、2,2,6-三甲基-4H-1,3-二噁英-4-酮为原料,酰化得到3-羰基-N-(噻唑-2-基)丁酰胺,再与3,4-二甲氧基苯乙胺缩合得到(E)-3-((3,4-二甲氧基苯乙基)氨基)-N-(噻唑-2-基)-2-丁烯酰胺,最后环合得到目标化合物1,总收率为79.4%.PCSK9is a clinically proven and effective target for the treatment of hypercholesterolemia.Inhibition of PCSK9 activity can significantly reduce plasma cholesterol level and delay the progression of atherosclerosis.Tetrahydroisoquinoline compound 1is an allosteric inhibitor of PCSK9with novel structure and unique mechanism of action.Taking 2-aminothiazole,2,2,6-trimethyl-4 H-1,3-dioxin-4-one as raw materials,acylated to obtain 3-carbonyl-N-(thiazol-2-yl)butyl amide,(E)-3-((3,4-dimethoxy-phenylethyl)amino)-N-(thiazol-2-yl)-2-butenamide was synthesized by condensation with 3,4-dimethoxy-phenylethyl amine,and the target compound 1was obtained by cyclization.The total yield was 79.4%.

关 键 词：四氢异喹啉类化合物 PCSK9 抑制剂 合成 

分 类 号：R938.8[医药卫生—生药学]