Discovery and preclinical evaluations of GST-HG131, a novel HBV antigen inhibitor for the treatment of chronic hepatitis B infection.

Abstract

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).

• Authors: Yanbin Hu, Fei Sun, Qiang Yuan, Jinhua Du, Lihong Hu, Zhengxian Gu, Qiong Zhou, Xiaoting Du, Shibo He, Ya Sun, Qian Wang, Lirong Fan, Lina Wang, Shaohua Qin, Shuhui Chen, Jian Li, Wenqiang Wu, John Mao, Yixin Zhou, Qiaoyun Zhou, George Zhang, Charles Z Ding
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 75 Pg. 128977 (11 01 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 36089112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Antigens, Surface
• Antiviral Agents
• DNA, Viral
• Hepatitis B e Antigens
• Hepatitis B Surface Antigens
• GST-HG131

Topics

• Animals
• Rats
• Antigens, Surface
• Antiviral Agents (pharmacology, therapeutic use)
• DNA, Viral
• Hepatitis B (drug therapy)
• Hepatitis B e Antigens (therapeutic use)
• Hepatitis B Surface Antigens
• Hepatitis B virus
• Hepatitis B, Chronic (drug therapy)