WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Bioorg Med Chem Lett. 2022 Nov 1;75:128977. doi: 10.1016/j.bmcl.2022.128977. Epub 2022 Sep 8.
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）仍然是全球范围内的一个重大健康挑战。目前的 CHB 治疗方法的治愈率不到 10%，大多数患者需要终身接受治疗。因此，治愈 CHB 是一个未满足的高医疗需求。HBV 表面抗原（HBsAg）的丢失和血清转换被认为是治愈的关键。RG7834 是一种新型的、口服生物利用的小分子，据报道可降低 HBV 抗原。基于 RG7834 的化学结构，我们设计并发现了一系列二氢苯并吡咯并恶嗪（DBP）系列的 HBV 抗原抑制剂。广泛的 SAR 研究使我们得到 GST-HG131，它在体外和体内均能显著降低 HBV 抗原（HBsAg 和 HBeAg）。与 RG7834 相比，GST-HG131 在大鼠毒理学研究中提高了安全性。有前途的抑制活性，加上动物安全性的提高，使 GST-HG131 值得在 2020 年进入临床开发（NCT04499443）。
