Ren Qingyun, Liu Xinchang, Luo Zhonghua, Li Jing, Wang Chaolei, Goldmann Siegfried, Zhang Jiancun, Zhang Yingjun
Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China.
Bioorg Med Chem. 2017 Feb 1;25(3):1042-1056. doi: 10.1016/j.bmc.2016.12.017. Epub 2016 Dec 19.
Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.
抑制乙型肝炎病毒（HBV）衣壳组装是开发慢性乙型肝炎（CHB）治疗药物的一种新策略。在此，我们描述了我们的先导化合物优化研究，包括一系列新型HBV衣壳组装抑制剂——杂芳基二氢嘧啶（HAP）抑制剂的合成、分子对接研究和构效关系（SAR）研究，以及发现了一种强效的HBV衣壳组装抑制剂GLS4（4-[2-溴-4-氟苯基]-6-[吗啉代甲基]-2-[2-噻唑基]-1,4-二氢嘧啶-5-羧酸乙酯），该药物目前处于临床2期。GLS4在HBV HepG2.2.15细胞试验中表现出强效抑制活性，EC值为1nM，并且它对各种耐药HBV病毒株也表现出高效力，EC值在10 - 20nM范围内，比典型的HBV聚合酶抑制剂如拉米夫定、替比夫定和恩替卡韦更有效。GLS4的药代动力学特征良好，包括急性毒性和重复毒性研究在内的安全性评估表明，GLS4足够安全以支持人体临床试验。
