论文总字数：31545字

摘 要

胆固醇（Cholesterol）是真核细胞膜结构的重要组成成分，它能够调节细胞膜的流动性，调控多种膜蛋白功能，并参与胞内转运以及跨膜信号的传导^[1,2]。人体胆固醇的均衡主要依靠体内内源性合成、小肠部位的吸收以及胆酸和粪便的排泄来维持，而体内胆固醇含量过高则会引起与动脉粥样硬化相关的心脑血管疾病的发生，从而导致人类的过早死亡。

血脂主要由血浆中的胆固醇、甘油三酯和磷脂组成，它主要是由于血液中总胆固醇（TC）和甘油三酯（TG）过高或高密度脂蛋白胆固醇（HDL-C）过低引起的。高血脂症又分为原发性及继发性高血脂症。高血脂症容易引起动脉粥样硬化，导致一系列心脑血管疾病，如心绞痛，冠心病，高血压，脑中风等^[3]。因此降低血液中的总胆固醇特别是低密度胆固醇含量是目前预防和治疗高脂血症的重要手段。Ezetimibe是目前唯一上市的胆固醇吸收抑制剂，它能够通过抑制小肠上皮NPC1L1的活性来阻断胆固醇转运系统，从而降低血浆中胆固醇。以NPC1L1为靶点的药物研发具有较好的应用前景。

目前，依折麦布是唯一上市的胆固醇吸收抑制剂，主要通过抑制小肠上皮细胞NPC1L1蛋白发挥作用，临床上与他汀类药物联合使用来治疗高血脂症。目前有研究发现依折麦布逆转动脉粥样硬化病变作用不明显，且存在一定的安全风险。所以，以NPC1L1蛋白为靶点的新型胆固醇吸收抑制剂的研究仍然十分迫切!

作为合成和研发抑制NPC1L1药物项目的一部分，本课题旨在合成具有新型骨架的胆固醇吸收抑制剂。利用本实验室前期的工作基础结合药物设计原理，我们尝试引入3,4-二芳基马来酰亚胺作为母核，此外引入大极性基团来降低药物的生物利用度，让他只在肠道内与NPC1L1的膜外区域结合，阻断胆固醇吸收，从而实现肠靶向性。设计并合成了一系列化合物，期待具有较好的抑制胆固醇吸收的活性。

关键词:高脂血症 胆固醇吸收抑制 NPC1L1 3,4-二芳基马来酰亚胺

Design and synthesis of cholesterol absorption inhibitor

ABSTRACT

Cholesterol is an important component of eukaryocyte membrane and plays an significant role in the functions of membrane proteins, membrane trafficking and transmembrane signalling processes. Cholesterol homeostasis is regulated by endogenous synthesis, absorption in the small intestine and excretion by cholic acid and faeces. High level of cholesterol in the body can induce the emergence of atherosclerotic cardiovascular disease and triggers early death.

Lipids mainly by plasma cholesterol, triglycerides and phospholipids, which is mainly due to the total blood cholesterol and triglyceride is too high, or high-density lipoprotein cholesterol induced lowly. Hyperlipidemia is divided into primary and secondary hyperlipidemia. Hyperlipidemia can increase biood viscosity resulting in atherosclerosis high blood presssure, liver damage, is the leading cause of coronary heart disease, myocardial infarction and ischemic stroke and other cardiovascular and cerebrovascular disease^[1]. Thus reducing the total cholesterol in the blood especially LDL-C level is an important means of prevention and treatment currently hyperlipidemia. Ezetimibe is the only cholesterol absorption inhibitor market, which can inhibit the activity of intestinal epithelial blocking NPC1L1 cholesterol transport system, thereby lowering plasma cholesterol. In NPC1L1 as a target of drug development have good prospects.

Currently, ezetimibe is the only marketable cholesterol absorption inhibitor and NPC1L1 protein was identified as the target of ezetimibe in 2004. Clinically, it can be administered as combinatory treatment with statins. However, therapeutic effect of ezetimibe is poor in the patients with atherosclerosis and ezetimibe has some security risks. So, there remains the demand for developing new cholesterol absorption inhibitors that can improve therapeutic efficacy and supply patients more choices.

As part of the research and development of drugs inhibiting NPC1L1 project, this study aimed at finding a cholesterol absorption inhibitor with a novel skeleton. Combined with the preliminary basis for the work of the laboratory and principles of rational drug design, we try to introduce 3,4-arylmaleimide as nucleus, in addition to the introduction of large polar groups to reduce the bioavailability of the drug, so that only NPC1L1 membrane binding outside the region in the intestine, blocking absorption of cholesterol in order to achieve intestinal targeting. Designed and synthesized a series of compounds expected to have better cholesterol absorption inhibitory activity.

Key Words: Hyperlipidemia; Cholesterol absorption inhibitor; NPC1L1; 3,4-Diarylmalei

目 录

摘 要 I

ABSTRACT II

第一章 研究背景 1

1.1 临床应用的传统调血脂药 1

1.2 抑制NPC1L1/Flotillin复合物的形成 3

1.3 课题简介 4

1.3.1 课题背景 4

1.3.2 课题特色与创新 5

第二章 目标化合物的设计 6

2.1 化合物的设计 6

第三章 目标化合物的合成 8

3.1 关键中间体的合成 8

3.2 结果与讨论 9

3.3 化合物的合成 10

第四章 化合物的合成及波谱数据 11

4.1 仪器与数据 11

4.2 实验操作和化合物波谱数据 11

第五章 总结与展望 24

参考文献 25

致 谢 38

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