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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
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