Synthesis and evaluation of N-sulfonylpiperidine-3-carboxamide derivatives as capsid assembly modulators inhibiting HBV in vitro and in HBV-transgenic mice

Jiaxin Yin(印家鑫); Zhongqi Feng（冯中奇）; Zhi Li（李治）; Jieli Hu; Yuan Hu; Xuefei Cai; Hui Zhou; Kai Wang; Ni Tang; Ailong Huang， Luyi Huang  

Highlights

•Preparation of sulfonylpiperidine based capsid assembly modulators as anti-HBV agents.

•C-49 induced the formation of genome-less empty capsid.

•C-49 suppressed HBV replication in stable, transient, and de novo infection cell models.

•C-49 exhibited anti-HBV activity across genotypes A‒D.

•C-49 efficiently inhibited HBV replication in HBV-transgenic mice without apparent hepatotoxicity.

Abstract

The hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been developed as effective anti-HBV agents in the treatment of chronic HBV infection by targeting the HBV core protein and inducing the formation of aberrant or morphologically normal capsid. However, some CAMs have been observed adverse events such as ALT flares and rash. Therefore, finding new CAMs is of great importance. In this report, we synthesized N-sulfonylpiperidine-3-carboxamides (SPCs) derivatives and evaluated their anti-HBV activities. Among the SPC derivatives, compound C-49 notably suppressed HBV replication in HepAD38, HepG2-HBV1.3 and HepG2-NTCP cells. Moreover, treatment with C-49 for 12 days exhibited potent anti-HBV activity (100 mg/kg; 2.42 log reduction of serum HBV DNA) in HBV-transgenic mice without apparent hepatotoxicity. Our findings provided a new SPC derivative as HBV capsid assembly modulator for developing safe and efficient anti-HBV therapy.

Keywords

HBVCore protein Sulfonylpiperidine Capsid assembly modulator Antiviral agent

Full text: https://www.sciencedirect.com/science/article/pii/S0223523423000569

Doi: https://doi.org/10.1016/j.ejmech.2023.115141