AB-452 / Arbutus - LARVOL DELTA

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. (PubMed, J Med Chem) - "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."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Pain

Structure-Activity Relationships and Discovery of (S)-6-Isopropyl-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic Acid (AB-452), a Novel Orally Available HBV RNA Destabilizer. (PubMed, J Med Chem) - "AB-452 showed acceptable tolerability in 28-day rat and dog toxicity studies, and a high degree of oral exposure in multiple species. Based on its in vitro and in vivo profiles, AB-452 was identified as a clinical development candidate."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNA1

Host poly(A) polymerases PAPD5 and PAPD7 provide two layers of protection that ensure the integrity and stability of hepatitis B virus RNA. (PubMed, J Virol) - "Here, we utilized a potent small-molecule AB-452 as a chemical probe, along with genetic analyses to dissect the individual roles of PAPD5/7 in HBV RNA stability...Herein, our antiviral and genetic studies using relevant HBV infection and replication models further characterize the interplays between the cis-element within the viral sequence and the trans-elements from the host factors. PAPD5/7 targeting inhibitors, with oral bioavailability, thus represent an opportunity to reduce HBsAg through destabilizing HBV RNA."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation