Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors

作者：Wuhong Chen, Feifei Liu, Qiliang Zhao, Xinna Ma, Dong Lu, Heng Li, Yanping Zeng, Xiankun Tong, Limin Zeng, Jia Liu, Li Yang, Jianping Zuo, Youhong Hu · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c00346 · 被引用次数：27 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Hepatitis Viruses Studies and Epidemiology

HBV capsid assembly has been viewed as an attractive target for new antiviral therapies against HBV. On the basis of a lead compound 4r, we further investigated this target to identify novel active compounds with appropriate anti-HBV potencies and improved pharmacokinetic (PK) properties. Structure–activity relationship studies based on metabolic pathways of 4r led to the identification of a phthalazinone derivative 19f with appropriate anti-HBV potencies (IC 50 = 0.014 ± 0.004 μM in vitro ), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of 19f resulted in a 2.67 log reduction of the HBV DNA viral load during a 4-week treatment with 150 mg/kg dosing twice daily.