Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4)
Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4)
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DOI：
10.1016/j.bmc.2016.12.017
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Zhang, Yingjun
中科院分区：
文献类型：
--
作者：
Ren, Qingyun;Liu, Xinchang;Zhang, Yingjun
抑制B型肝炎病毒（HBV）衣壳组装是开发慢性B型肝炎（CH B）治疗剂的新策略。本文介绍了我们的先导化合物优化研究，包括一系列新的杂芳基二氢嘧啶（HAP）抑制剂的合成、分子对接研究和构效关系（SAR）研究，以及一个有效的HBV衣壳组装抑制剂GLS 4的发现（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-甲酸乙酯），其目前处于临床2期。GLS 4在HBV HepG2.2.15细胞试验中表现出有效的抑制活性，EC 50值为1 nM，并且它还表现出对各种耐药HBV病毒株的高效力，EC 50值在10-20 nM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。GLS 4的药代动力学特征良好，包括急性毒性和重复毒性研究的安全性评价表明GLS 4足够安全，可支持人体临床试验。(C)2016爱思唯尔有限公司版权所有。
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-fluoropheny1]-6-[morpholinomethy1]-242-thiazoly1]-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 EC50 value of 1 nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20 nM, 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. (C) 2016 Elsevier Ltd. All rights reserved.