2. Academic Validation
  3. 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

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.
Dimitar Gotchev 1,  Shuai Chen 1,  Benjamin Dugan 1,  Bruce D Dorsey 1,  Xu Wang 1,  Muhammad Sheraz 1,  Rose Kowalski 1,  Fei Liu 1,  Sunny Tang 1,  Tim Chiu 1,  Troy Harasym 1,  Ingrid E Graves 1,  Emily P Thi 1,  Jeremy D Mason 1,  Nathan Overholt 1,  Ravi Dugyala 1,  Angela M Lam 1,  Andrew G Cole 1,  Michael J Sofia 1
Affiliations

Affiliation

  • 1 Arbutus Biopharma, Warminster, Pennsylvania 18974, United States.
PMID: 39513566 DOI: 10.1021/acs.jmedchem.4c01928
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159987
    HBV Inhibitor
    HBV