2. Academic Validation
  3. 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)

  • Bioorg Med Chem. 2017 Feb 1;25(3):1042-1056. doi: 10.1016/j.bmc.2016.12.017.
Qingyun Ren 1,  Xinchang Liu 1,  Zhonghua Luo 2,  Jing Li 2,  Chaolei Wang 1,  Siegfried Goldmann 3,  Jiancun Zhang 4,  Yingjun Zhang 5
Affiliations

Affiliations

  • 1 Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
  • 2 Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China.
  • 3 Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: sigi@hecpharm.com.
  • 4 Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 5 Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: zhangyingjun@hecpharm.com.
PMID: 28082068 DOI: 10.1016/j.bmc.2016.12.017
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.

Keywords

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

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