Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
Eur J Med Chem. 2017 Oct 20;139:201-213. doi: 10.1016/j.ejmech.2017.08.012. Epub 2017 Aug 4.
A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with ICs less than 10 μM. Among them, compound 20 (IC = 2.3 μM) had the most potent biological activity, and effectively ameliorated plasma lipid levels of human adipose tissue specific CETP transgenic (ap2-CETPTg) mice and guinea pigs. Additional safety evaluation (no blood pressure elevation in guinea pigs) and pharmacokinetics studies indicated that the potential druggability for compound 20 which is a promising lead for development of a new class of CETP inhibitors for the treatment of dyslipidemia.
设计、合成并评价了一系列五环三萜 3β-酯衍生物，作为治疗血脂异常的新型胆固醇酯转移蛋白（CETP）抑制剂。体外筛选实验表明，30 个化合物中有 5 个具有中等抑制人 CETP 活性，IC 小于 10 μM。其中，化合物 20（IC = 2.3 μM）具有最强的生物活性，有效改善了人脂肪组织特异性 CETP 转基因（ap2-CETPTg）小鼠和豚鼠的血浆脂质水平。额外的安全性评估（豚鼠血压无升高）和药代动力学研究表明，化合物 20 具有潜在的成药性，是开发治疗血脂异常的新型 CETP 抑制剂的有前途的先导化合物。
