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.

中文翻译：

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（S）-5-（叔丁基）-11-（二氟甲氧基）-9-甲氧基-2-氧代-1,2,5,6-四氢吡啶[2′，1′：2,3]咪唑[4,5-h]喹啉-3-羧酸（AB-161）的结构-活性关系和发现，这是一种新型口服且以肝脏为中心的HBV RNA去稳定剂


降低共价闭合环状 DNA （cccDNA） 和整合基因组的乙型肝炎表面抗原 （HBsAg） 水平可以减少乙型肝炎病毒 （HBV） 感染的持续性。由于 HBV 复制发生在肝脏中，并且为了改善使用具有高全身暴露的第一代三环 4-吡啶酮 PAPD5/7 抑制剂 （AB-452） 观察到的周围神经病变，我们专注于增加肝细胞浓度和降低血浆水平。降低 HBsAg 水平的新型 PAPD5/7 抑制剂系列的优化导致了四环 2-吡啶酮 AB-161，它在体外和体内与 AB-452 相似，但显示出显着更高的啮齿动物肝脏与血浆比率。AB-161 在 60 天后高达 45 mg/kg 的狗中没有神经行为影响，这与 AB-452 不同，AB-452 在第 14 天时以较低剂量观察到这些影响。然后，AB-161 被推进到 90 天的 GLP 毒理学研究中，其中改善的神经毒性特征仍然存在，但出现了生殖问题，导致停药。