Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors

Abstract

HBV capsid assembly has been viewed as an attractive target for new antiviral therapies against HBV. On the basis of a lead compound <b>4r</b>, 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 <b>4r</b> led to the identification of a phthalazinone derivative <b>19f</b> with appropriate anti-HBV potencies (IC₅₀ = 0.014 ± 0.004 μM <i>in vitro</i>), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of <b>19f</b> 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.