Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Chronic hepatitis B (CHB) remains a significant global health concern.
• Current therapies for CHB have limitations, necessitating novel treatment strategies.
• HBV capsid assembly modulators offer a promising therapeutic approach by inhibiting viral replication.

Purpose of the Study:

• To develop and optimize novel isoquinolinone-based HBV capsid assembly modulators.
• To investigate the structure-activity relationship (SAR) of these compounds.
• To evaluate the antiviral efficacy and pharmacokinetic properties of lead candidates.

Main Methods:

• Protein X-ray crystallography was used to analyze the binding mode of modulators to the HBV core protein.
• Structure-based drug design was employed to introduce constraints for optimizing binding conformation.
• Cellular assays (HepDE19) were used to determine EC50 values against HBV DNA.
• ADME and pharmacokinetic studies were conducted in vitro and in vivo.
• An in vivo hydrodynamic injection mouse model was used to assess oral efficacy.

Main Results:

• Optimized isoquinolinone analogues achieved single-digit nanomolar EC50 values in reducing HBV DNA.
• Lead compound 12e demonstrated a 3 log10 decline in serum HBV DNA at 1 mg/kg/day in a mouse model.
• Compounds exhibited favorable ADME and pharmacokinetic profiles, supporting oral administration.
• Activity was maintained against clinically relevant HBV core protein variants (T33N, I105T).

Conclusions:

• Isoquinolinone-based HBV capsid assembly modulators represent a promising new class of antiviral agents.
• Structure-based optimization has led to potent and orally bioavailable drug candidates.
• These compounds show significant potential for treating chronic hepatitis B infection, including in cases with resistant variants.