核衣壳抑制剂wx～066

newchinabok

https://liverlearning.aasld.org/ ... apsid.assembly.html

newchinabok

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.

齐欢畅

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.

antiHBVren

TLE：发现高效和选择性的衣壳装配抑制剂（WX-066）用于治疗慢性HBV感染
赞助 - 本研究赞助此摘要未获得赞助请说明）：
无锡AppTec（上海）有限公司
齐鲁药业有限公司山东省小分子靶向药物重点实验室
摘要：
背景：慢性乙型肝炎（CHB）感染是一个重大的全球健康问题，导致肝纤维化，肝硬化甚至肝细胞癌，影响全球超过3.5亿人。 HBV衣壳蛋白在HBV复制中起重要作用。在这里，我们报告WX-066作为一种新型的HBV衣壳装配抑制剂，具有较强的抗HBV体外和体内复制活性。
方法：合成一系列新型融合的3,5,6,7-四氢吡咯并[1,2-c]嘧啶并通过HBV复制试验进行评估。在HBV衣壳组装淬灭测定中测试WX-066中断病毒核心蛋白组装，抑制HepG2.2.15细胞中HBV复制。在Balb / c小鼠中测定药代动力学参数。进一步评估WX-066针对流体动力注射（HDI）小鼠模型中的HBV感染。
结果：WX-066在EC50 = 5nM的HepG2.2.15细胞中抑制HBV复制。 WX-066显示中等血浆清除率（Cl）（21 mL min-1 kg-1）。在小鼠中具有高L / P比（9：1）的54％的良好的口服生物利用度（F）。此外，与载体相比，流体动力注射（HDI）模型显示WX-066治疗在第5天和第7天分别实现小鼠血浆中的2.57和2.11log10病毒DNA减少，并且在小鼠中减少了0.68log10病毒DNA肝脏在第7天。
结论：WX-066是一种有效的HBV衣壳组装抑制剂。在小鼠体内具有较高的L / P比值，具有优异的药代动力学特性。其HDI模型证实其活性HBV功效。这些结果支持WX-066作为慢性乙型肝炎患者潜在的新型治疗剂的临床开发。

hbv_challenger

记号

hp121

国产

windu

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