五环三萜类CETP抑制剂的设计、合成及活性评价

Dyslipidemia is a well-known and major risk factor for atherosclerosis (AS). Statins are the first-line drug therapy in the treatment of hypercholesterolemia, but exhibiting a number of serious adverse effects. Cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport process, and mediates the metabolic processes between high density lipoprotein cholesterol and low density lipoprotein cholesterol. Some current small molecule CETP inhibitors are expected to be developed as novel lipid-lowering and anti-atherosclerosis agents, but existing some lacks, such as high lipid solubility, low bioavailability and limited effectiveness in clinical trials. Until now, no any one of CETP inhibitors has passed the FDA's approval. According to the preliminary study, some 3β-ester derivatives of pentacyclic triterpenes (PTs) were confirmed as potential CETP inhibitors. Among of them, compound 10 exhibited good inhibitory activity (IC50 = 3.5 μM). On this basis, with compound 10 as the leading molecule, this project aimed at developing PTs as novel CETP inhibitors with employing target-based and structure-based drug design. This project will find some potential candidate drug molecules through many rounds of structure modification and biological evaluation, and then comprehensively investigate their lipid-lowering effects. We are confident that this project may bring us new insights to solve the deficiencies of current CETP inhibitors and statins, further complete the lipid-lowering mechanism of PTs, and lay the foundation for developing PTs as lipid-lowering and anti-atherosclerosis agents.

血脂异常是动脉粥样硬化（AS）的重要危险因素，虽然他汀是临床调血脂治疗的一线用药，但存在许多不良反应。胆固醇酯转运蛋白（CETP）是胆固醇逆转运过程中协调脂质转运的核心蛋白，其抑制剂有可能成为新型的调血脂及抗AS药物，但现有CETP抑制剂存在如脂溶性高、生物利用度低、临床疗效有限等众多问题。申请人前期研究发现五环三萜3β-酯衍生物是一类潜在的CETP抑制剂，其中化合物10表现出较好的抑制活性（IC50 = 3.5 μM）。在此基础上，本项目以化合物10为先导分子，采用基于靶点和基于结构的药物设计手段，设计合成新型的五环三萜类CETP抑制剂，经过多轮次的结构修饰与活性评价，发现具有潜力的候选药物分子，并全面考察其调血脂功效。本研究将为解决现有CETP抑制剂的不足，以及弥补他汀的临床应用缺陷提供新的研究思路，同时进一步完善五环三萜调血脂的药理学网络，为开发五环三萜类调血脂及抗AS药物奠定基础。

血脂异常是动脉粥样硬化（AS）的重要危险因素，虽然他汀是临床调血脂治疗的一线用药，但存在许多不良反应。胆固醇酯转运蛋白（CETP）是胆固醇逆转运过程中协调脂质转运的核心蛋白，其抑制剂有可能成为新型的调血脂及抗AS药物，但现有CETP抑制剂存在如脂溶性高、生物利用度低、临床疗效有限等众多问题。本项目采用基于靶点和基于结构的药物设计手段，设计合成了一系列五环三萜3β-酯衍生物作为潜在的CETP抑制剂，其中，化合物20（IC50 = 2.3 μM）和U12（IC50 = 2.1 μM）表现出较好的CETP抑制活性。化合物20能够有效调节Ap2-CETP转基因小鼠和豚鼠模型的血脂水平。此外，化合物20不存在血压升高的风险，并且具有较好的药代动力学参数，其AUC0-48值为9337.83 ± 2152.23 ng/mL*h，半衰期t1/2 = 18.75 ± 5.15 h。化合物20有望成为治疗血脂异常的候选药物分子。分子对接研究展示了五环三萜类CETP 抑制剂与蛋白的结合模式，总结了此类小分子抑制剂的构效关系，对新型五环三萜类CETP抑制剂的后续设计和结构优化具有十分重要的指导意义。本项目将为解决现有CETP抑制剂的不足，以及弥补他汀的临床应用缺陷提供新的研究思路，同时进一步完善五环三萜调血脂的药理学网络，为开发五环三萜类调血脂及抗AS药物奠定基础。