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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Associated data

  • ClinicalTrials.gov/NCT04499443