Chronic hepatitis B (CHB) remains a significant health challenge worldwide. The current treatments for CHB achieve less than 10% cure rates, majority of the patients are on therapy for life. Therefore, cure of CHB is a high unmet medical need. HBV surface antigen (HBsAg) loss and seroconversion are considered as the key for the cure. RG7834 is a novel, orally bioavailable small molecule reported to reduce HBV antigens. Based on RG7834 chemistry, we designed and discovered a series of dihydrobenzopyridooxazepine (DBP) series of HBV antigen inhibitors. Extensive SAR studies led us to GST-HG131 with excellent reduction of HBV antigens (both HBsAg and HBeAg) in vitro and in vivo. GST-HG131 improved safety in rat toxicology studies over RG7834. The promising inhibitory activity, together with animal safety enhancement, merited GST-HG131 progressed into clinical development in 2020 (NCT04499443).

慢性乙型肝炎 (CHB) 仍然是全世界面临的重大健康挑战。目前慢性乙型肝炎的治疗治愈率不到10%，大多数患者需要终身治疗。因此，治愈慢性乙型肝炎是一个未满足的医疗需求。乙型肝炎表面抗原（HBsAg）消失和血清转化被认为是治愈的关键。RG7834 是一种新型口服生物利用小分子，据报道可减少 HBV 抗原。基于RG7834化学，我们设计并发现了一系列二氢苯并吡啶并恶氮卓（DBP）系列HBV抗原抑制剂。广泛的 SAR 研究使我们发现 GST-HG131在体外和体内都能出色地降低 HBV 抗原（HBsAg 和 HBeAg）。与 RG7834 相比，GST-HG131 提高了大鼠毒理学研究的安全性。具有前景的抑制活性，加上动物安全性的增强，使得 GST-HG131 值得在 2020 年进入临床开发（NCT04499443）。