Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
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
Abstract
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 (IC50 = 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.