Discovery, optimization and biological evaluation of novel HBsAg production inhibitors

Hepatitis B virus (HBV) infection is a major global health problem. HBsAg inhibitors are expected to reduce the production of HBsAg via inhibiting host proteins PAPD5 & PAPD7 and finally achieve the ideal goal of “functional cure”. In this work, a series of tetrahydropyridine (THP) derivatives with a bridged ring were synthesized and evaluated for their inhibiting HBsAg production and HBV DNA activity. Among them, compound 17i was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency (HBV DNA EC50 = 0.018 μM, HBsAg EC50 = 0.044 μM) and low toxicity (CC50 > 100 μM). Moreover, 17i exhibited favorable in vitro/in vivo DMPK properties in mice. 17i could also significantly reduce serum HBsAg and HBV DNA levels (1.08 and 1.04 log units, respectively) in HBV transgenic mice. [Display omitted] •A series of tetrahydropyridine (THP) derivatives with bridged fragments were designed and synthesized.•The target compounds showed potent antiHBV activity.•Compound 17i was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency and low toxicity.•Compound 17i exhibited favorable in vitro/in vivo DMPK properties in mice.•Compound 17i could also significantly reduce serum HBsAg and HBV DNA levels in HBV transgenic mice.