TITLE: Discovery of A Highly Potent and Selective Capsid Assembly Inhibitor (WX-066) For the Treatment of Chronic HBV Infection
SPONSORSHIP - THIS STUDY WAS SPONSORED BYIF THIS ABSTRACT WAS NOT SPONSORED PLEASE INDICATE):
WuXi AppTec (Shanghai) Co., Ltd
Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd
ABSTRACT BODY:
Background: Chronic Hepatitis B (CHB) infection is a significant global health problem, which leads to liver fibrosis, cirrhosis and even hepatocellular carcinoma, and affects over 350 million people worldwide. HBV capsid protein plays essential roles in HBV replication. Here we report WX-066 as a novel HBV capsid assembly inhibitor with strong activity against HBV replication in vitro and in vivo.
Methods: A series of novel fused 3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidines were synthesized and evaluated by the HBV replication assays. WX-066 was tested for interruption of the virus core protein assembly in an HBV capsid assembly quenching assay, inhibition of HBV replication in HepG2.2.15 cells. Pharmacokinetic parameters were determined in Balb/c mice. WX-066 was further assessed against HBV infection in the hydrodynamic injection (HDI) mouse model.
Results: WX-066 inhibited HBV replication in HepG2.2.15 cells with EC50 = 5 nM. WX-066 exhibited moderate plasma clearance (Cl) (21 mL min−1 kg−1). It possessed good oral bioavailability (F) of 54% with high L/P ratio (9:1) in mice. Furthermore, In comparison with the vehicle, the hydrodynamic injection (HDI) model demonstrated that WX-066 treatment achieved 2.57 and 2.11 log10 viral DNA reduction in the mice plasma on days 5 and 7, respectively, and reduced 0.68 log10 viral DNA in the mice livers on day 7.
Conclusions: WX-066 is a potent HBV capsid assembly inhibitor. it showed excellent pharmacokinetic properties in vivo with high L/P ratio in mice. Its active HBV efficacy was demonstrated by the HDI model. These results support the clinical development of WX-066 as a potential new therapeutic agent for chronic hepatitis B patients.作者: 齐欢畅 时间: 2017-10-26 21:18
TLE: Discovery of A Highly Potent and Selective Capsid Assembly Inhibitor (WX-066) For the Treatment of Chronic HBV Infection
SPONSORSHIP - THIS STUDY WAS SPONSORED BYIF THIS ABSTRACT WAS NOT SPONSORED PLEASE INDICATE):
WuXi AppTec (Shanghai) Co., Ltd
Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd
ABSTRACT BODY:
Background: Chronic Hepatitis B (CHB) infection is a significant global health problem, which leads to liver fibrosis, cirrhosis and even hepatocellular carcinoma, and affects over 350 million people worldwide. HBV capsid protein plays essential roles in HBV replication. Here we report WX-066 as a novel HBV capsid assembly inhibitor with strong activity against HBV replication in vitro and in vivo.
Methods: A series of novel fused 3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidines were synthesized and evaluated by the HBV replication assays. WX-066 was tested for interruption of the virus core protein assembly in an HBV capsid assembly quenching assay, inhibition of HBV replication in HepG2.2.15 cells. Pharmacokinetic parameters were determined in Balb/c mice. WX-066 was further assessed against HBV infection in the hydrodynamic injection (HDI) mouse model.
Results: WX-066 inhibited HBV replication in HepG2.2.15 cells with EC50 = 5 nM. WX-066 exhibited moderate plasma clearance (Cl) (21 mL min−1 kg−1). It possessed good oral bioavailability (F) of 54% with high L/P ratio (9:1) in mice. Furthermore, In comparison with the vehicle, the hydrodynamic injection (HDI) model demonstrated that WX-066 treatment achieved 2.57 and 2.11 log10 viral DNA reduction in the mice plasma on days 5 and 7, respectively, and reduced 0.68 log10 viral DNA in the mice livers on day 7.
Conclusions: WX-066 is a potent HBV capsid assembly inhibitor. it showed excellent pharmacokinetic properties in vivo with high L/P ratio in mice. Its active HBV efficacy was demonstrated by the HDI model. These results support the clinical development of WX-066 as a potential new therapeutic agent for chronic hepatitis B patients.作者: antiHBVren 时间: 2017-10-27 11:41
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