Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4)

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• 作者：Qingyun Ren^a ; ^b ; Xinchang Liu^a ; ^b ; Zhonghua Luo^a ; Jing Li^a ; Chaolei Wang^a ; ^b ; Siegfried Goldmann^a ; ^{sigi@hecpharm.com} ; Jiancun Zhang^c ; Yingjun Zhang^a ; ^{zhangyingjun@hecpharm.com}
• 关键词：HBV ; Capsid assembly inhibitor ; SAR ; GLS4 ; Pharmacokinetics ; Safety evaluation
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1042-1056
• 全文大小：3202 K
• 卷排序：25

文摘

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 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.