Structure–Activity Relationships and Discovery of (<i>S</i>)-5-(<i>tert</i>-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2′,1′:2,3]imidazo[4,5-<i>h</i>]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-C

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 (<b>AB-452</b>) 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 <b>AB-161</b>, which was similarly potent to <b>AB-452</b> <i>in vitro</i> and <i>in vivo</i> but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with <b>AB-161</b> in dogs up to 45 mg/kg after 60 days, unlike with <b>AB-452</b>, where these were observed at lower doses by day 14. <b>AB-161</b> was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.