Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
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作为新型乙型肝炎病毒衣壳抑制剂的酞嗪酮衍生物的发现
DOI：
10.1021/acs.jmedchem.0c00346
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发表时间：
2020-08-13
影响因子：
7.3
通讯作者：
Hu, Youhong
中科院分区：
文献类型：
--
作者：
Chen, Wuhong;Liu, Feifei;Hu, Youhong
HBV衣壳组装已被视为抗HBV的新的抗病毒治疗的有吸引力的靶点。在先导化合物4 r的基础上，我们进一步研究了这一目标，以确定具有适当抗HBV效力和改善药代动力学（PK）特性的新型活性化合物。基于4 r代谢途径的结构-活性关系研究鉴定了具有适当抗HBV效力的二氮杂萘酮衍生物19 f（体外IC 50 = 0.014 +/- 0.004 μ M），其证明了高口服生物利用度和肝脏暴露。在AAV-HBV/小鼠模型中，191的给药导致在150 mg/kg每日两次给药的4周治疗期间HBV DNA病毒载量的2.67 log减少。
HBV capsid assembly has been viewed as an attractive target for new antiviral therapies against HBV. On the basis of a lead compound 4r, we further investigated this target to identify novel active compounds with appropriate anti-HBV potencies and improved pharmacokinetic (PK) properties. Structure-activity relationship studies based on metabolic pathways of 4r led to the identification of a phthalazinone derivative 19f with appropriate anti-HBV potencies (IC50 = 0.014 +/- 0.004 mu M in vitro), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of 191 resulted in a 2.67 log reduction of the HBV DNA viral load during a 4-week treatment with 150 mg/kg dosing twice daily.