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

被引：5

作者：

Hu, Yanbin ^{[1
]}

Sun, Fei ^{[1
]}

Yuan, Qiang ^{[1
]}

Du, Jinhua ^{[1
]}

Hu, Lihong ^{[1
]}

Gu, Zhengxian ^{[2
]}

Zhou, Qiong ^{[2
]}

Du, Xiaoting ^{[2
]}

He, Shibo ^{[2
]}

Sun, Ya ^{[2
]}

Wang, Qian ^{[2
]}

Fan, Lirong ^{[2
]}

Wang, Lina ^{[2
]}

Qin, Shaohua ^{[2
]}

Chen, Shuhui ^{[2
]}

Li, Jian ^{[2
]}

Wu, Wenqiang ^{[3
]}

Mao, John ^{[3
]}

Zhou, Yixin ^{[3
]}

Zhou, Qiaoyun ^{[3
]}

Zhang, George ^{[3
]}

Ding, Charles Z. ^{[2
]}

机构：

[1] WuXi AppTec, 666 Gaoxin Rd,East Lake High tech Dev Zone, Wuhan 430075, Peoples R China

[2] WuXi AppTec, 288 Fute Zhong Rd,Waigaoqiao Free Trade Zone, Shanghai 200131, Peoples R China

[3] Fujian Akeylink Biotechnol Co Ltd, Fuzhou, Fujian, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 75卷

关键词：

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

D O I：

10.1016/j.bmcl.2022.128977

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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).

引用

页数：5

共 15 条

[1] New Approaches to the Treatment of Chronic Hepatitis B [J].

Alexopoulou, Alexandra ;

Vasilieva, Larisa ;

Karayiannis, Peter .

JOURNAL OF CLINICAL MEDICINE, 2020, 9 (10) :1-23

[2]

[Anonymous], 2021, WHO HEP B FACT SHEET

[3]

[Anonymous], CLIN TRIAL GST HG131

[4] Hepatitis B cure: How and when [J].

Dusheiko, Geoffrey .

LIVER INTERNATIONAL, 2021, 41 :24-29

[5] HBV and the immune response [J].

Ferrari, Carlo .

LIVER INTERNATIONAL, 2015, 35 :121-128

[6] Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action [J].

Han, Xingchun ;

Zhou, Chengang ;

Jiang, Min ;

Wang, Yongguang ;

Wang, Jianhua ;

Cheng, Zhanling ;

Wang, Min ;

Liu, Yongqiang ;

Liang, Chungen ;

Wang, Jianping ;

Wang, Zhanguo ;

Weikert, Robert ;

Lv, Wenzhe ;

Xie, Jianxun ;

Yu, Xin ;

Zhou, Xue ;

Luangsay, Souphalone ;

Shen, Hong C. ;

Mayweg, Alexander V. ;

Javanbakht, Hassan ;

Yang, Song .

JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (23) :10619-10634

[7] Perspectives and limitations for nucleo(t)side analogs in future HBV therapies [J].

Levrero, Massimo ;

Subic, Miroslava ;

Villeret, Francois ;

Zoulim, Fabien .

CURRENT OPINION IN VIROLOGY, 2018, 30 :80-89

[8]

Li X, 2022, ANTIMICROB AGENTS CH, V11

[9]

Lok AS, 2017, HEPATOLOGY, V66, P1296, DOI [10.1016/j.jhep.2017.05.008, 10.1002/hep.29323]

[10] An Overview of Hepatitis B Virus Surface Antigen Secretion Inhibitors [J].

Mohebbi, Alireza ;

Lorestani, Nazanin ;

Tahamtan, Alireza ;

Kargar, Niki L. ;

Tabarraei, Alijan .

FRONTIERS IN MICROBIOLOGY, 2018, 9

← 1 2 →