Structure-Activity Relationships and Discovery of (S)-5-(tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2',1':2,3]imidazo[4,5- h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer

J Med Chem. 2024 Nov 28;67(22):20467-20494. doi: 10.1021/acs.jmedchem.4c01928. Epub 2024 Nov 8.

Abstract

Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor (AB-452) having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone AB-161, which was similarly potent to AB-452 in vitro and in vivo but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with AB-161 in dogs up to 45 mg/kg after 60 days, unlike with AB-452, where these were observed at lower doses by day 14. AB-161 was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / chemistry
  • Antiviral Agents* / pharmacokinetics
  • Antiviral Agents* / pharmacology
  • Dogs
  • Drug Discovery
  • Hepatitis B Surface Antigens / metabolism
  • Hepatitis B virus* / drug effects
  • Hepatitis B virus* / genetics
  • Humans
  • Liver* / drug effects
  • Liver* / metabolism
  • Male
  • Mice
  • Quinolines / chemistry
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology
  • RNA, Viral
  • Rats
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Quinolines
  • RNA, Viral
  • Hepatitis B Surface Antigens