title: Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
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 EC50value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50values 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.
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
authors.forename: Xinchang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China; Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, China.
authors.forename: Chaolei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: sigi@hecpharm.com.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Goldmann
authors.affiliation: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Jiancun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Sunshine Lake Pharma Co., Ltd, Dong Guan 523808, China. Electronic address: zhangyingjun@hecpharm.com.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D011743:Pyrimidines; D013844:Thiazoles; C588160:ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(2-thiazolyl)-1,4-dihydropyrimidine-5-carboxylate
keywords: Capsid assembly inhibitor; GLS4; HBV; Pharmacokinetics; SAR; Safety evaluation