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. 2022 Nov 1:75:128977.
doi: 10.1016/j.bmcl.2022.128977. Epub 2022 Sep 8.

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

Yanbin Hu  1 , Fei Sun  1 , Qiang Yuan  1 , Jinhua Du  1 , Lihong Hu  1 , Zhengxian Gu  2 , Qiong Zhou  2 , Xiaoting Du  2 , Shibo He  2 , Ya Sun  2 , Qian Wang  2 , Lirong Fan  2 , Lina Wang  2 , Shaohua Qin  2 , Shuhui Chen  2 , Jian Li  2 , Wenqiang Wu  3 , John Mao  3 , Yixin Zhou  3 , Qiaoyun Zhou  3 , George Zhang  3 , Charles Z Ding  4
Affiliations

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

Yanbin Hu et al. Bioorg Med Chem Lett. .

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).

Keywords: Chronic hepatitis B (CHB); GST-HG131; HBV cure; HBV surface antigen inhibitor; HBsAg.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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