15/10/02说明:此前论坛服务器频繁出错,现已更换服务器。今后论坛继续数据库备份,不备份上传附件。

肝胆相照论坛

 

 

肝胆相照论坛 论坛 学术讨论& HBV English 乙型肝炎病毒衣壳组装抑制剂的发现导致基于杂芳基二氢嘧 ...
查看: 637|回复: 1
go

乙型肝炎病毒衣壳组装抑制剂的发现导致基于杂芳基二氢嘧

Rank: 8Rank: 8

现金
62111 元 
精华
26 
帖子
30441 
注册时间
2009-10-5 
最后登录
2022-12-28 

才高八斗

发表于 2017-1-15 21:24 |显示全部帖子
Bioorg Med Chem. 2016 Dec 19. pii: S0968-0896(16)31201-9. doi: 10.1016/j.bmc.2016.12.017. [Epub ahead of print]
Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
Ren Q1, Liu X1, Luo Z2, Li J2, Wang C1, Goldmann S3, Zhang J4, Zhang Y5.
Author information

    1Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
    2Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China.
    3Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: [email protected].
    4Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
    5Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: [email protected].

Abstract

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 EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 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.

Copyright © 2016 Elsevier Ltd. All rights reserved.
KEYWORDS:

Capsid assembly inhibitor; GLS4; HBV; Pharmacokinetics; SAR; Safety evaluation

PMID:
    28082068
DOI:
    10.1016/j.bmc.2016.12.017

Rank: 8Rank: 8

现金
62111 元 
精华
26 
帖子
30441 
注册时间
2009-10-5 
最后登录
2022-12-28 

才高八斗

发表于 2017-1-15 21:25 |显示全部帖子
Bioorg Med Chem。 2016十二月19. pii:S0968-0896(16)31201-9。 doi:10.1016 / j.bmc.2016.12.017。 [打印前的电子版]
乙型肝炎病毒衣壳组装抑制剂的发现导致基于杂芳基二氢嘧啶的临床候选人(GLS4)。
Ren Q1,Liu X1,Luo Z2,Li J2,Wang C1,Goldmann S3,Zhang J4,Zhang Y5。
作者信息

    1阳泉湖制药有限公司,东莞523808;抗感染创新部,新药研究所,HEC制药集团,东莞523871。
    2阳泉湖制药有限公司,东莞523808。
    三阳湖制药有限公司,东莞523808。电子地址:[email protected]
    4中国科学院广州生物医学与健康研究所,广州510530。
    5阳阳湖制药有限公司,东莞523808。电子地址:[email protected]

抽象

抑制乙型肝炎病毒(HBV)衣壳组装是慢性乙型肝炎(CHB)治疗的发展的新策略。在这里我们描述了我们的先导优化研究,包括一系列新型杂芳基二氢嘧啶(HAP)抑制剂的HBV衣壳装配抑制剂的合成,分子对接研究和结构活性关系(SAR)研究,以及发现一种有效的HBV衣壳装配抑制剂的GLS4(现在处于临床阶段的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) 2.GLS4在HBV HepG2.2.15细胞测定中显示出有效的抑制活性,EC 50值为1nM,并且对各种耐药性HBV病毒株显示出高效力,EC 50值在10-20nM的范围内,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。 GLS4的药代动力学特征是有利的,并且包括急性毒性和重复毒性研究的安全性评价表明GLS4足够安全以支持人类的临床实验。

版权所有©2016 Elsevier Ltd.保留所有权利。
关键词:

衣壳装配抑制剂; GLS4; HBV;药代动力学; SAR;安全评价

PMID:
    28082068
DOI:
    10.1016 / j.bmc.2016.12.017
你需要登录后才可以回帖 登录 | 注册

肝胆相照论坛

GMT+8, 2024-3-29 01:15 , Processed in 0.013508 second(s), 11 queries , Gzip On.

Powered by Discuz! X1.5

© 2001-2010 Comsenz Inc.