Approved therapies for hepatitis B virus (HBV) treatment include nucleos(t)ides and interferon alpha (IFN-α) which effectively suppress viral replication, but they rarely lead to cure. Expression of viral proteins, especially surface antigen of the hepatitis B virus (HBsAg) from covalently closed circular DNA (cccDNA) and the integrated genome, is believed to contribute to the persistence of HBV. This work focuses on therapies that target the expression of HBV proteins, in particular HBsAg, which differs from current treatments. Here we describe the identification of AB-452, a dihydroquinolizinone (DHQ) analogue. AB-452 is a potent HBV RNA destabilizer by inhibiting PAPD5/7 proteins in vitro with good in vivo efficacy in a chronic HBV mouse model. 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.

中文翻译：

---

(S)-6-异丙基-2-甲氧基-3-(3-甲氧基丙氧基)-10-氧代-5,10-二氢-6H-吡啶并[1,2-h][1,2-h]的构效关系和发现[1, 7]萘啶-9-羧酸 (AB-452)，一种新型口服 HBV RNA 去稳定剂

已批准的乙型肝炎病毒（HBV）治疗方法包括核苷（酸）和干扰素α（IFN-α），它们可以有效抑制病毒复制，但很少能治愈。病毒蛋白的表达，尤其是来自共价闭合环状 DNA (cccDNA) 和整合基因组的乙型肝炎病毒表面抗原 (HBsAg)，被认为有助于 HBV 的持续存在。这项工作的重点是针对 HBV 蛋白表达的疗法，特别是 HBsAg，这与目前的疗法不同。在这里，我们描述了二氢喹嗪酮 (DHQ) 类似物AB-452的鉴定。AB-452是一种有效的 HBV RNA 去稳定剂，可在体外抑制 PAPD5/7 蛋白，在慢性 HBV 小鼠模型中具有良好的体内疗效。AB-452在 28 天的大鼠和狗毒性研究中显示出可接受的耐受性，并且在多个物种中具有高度的口服暴露。根据其体外和体内概况，AB-452被确定为临床开发候选药物。