酞嗪酮衍生物作为新型乙型肝炎病毒衣壳抑制剂的发现

StephenW

Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
Wuhong Chen  1 , Feifei Liu  2   3 , Qiliang Zhao  1   3 , Xinna Ma  2   4 , Dong Lu  1 , Heng Li  2   3 , Yanping Zeng  1   3 , Xiankun Tong  2 , Limin Zeng  1 , Jia Liu  1 , Li Yang  2 , Jianping Zuo  2   4 , Youhong Hu  1   3   5
Affiliations
Affiliations

    1
    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
    2
    Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China.
    3
    University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
    4
    Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
    5
    School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, Hangzhou 310024, China.

    PMID: 32692159 DOI: 10.1021/acs.jmedchem.0c00346

Abstract

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 μM in vitro), which demonstrated high oral bioavailability and liver exposure. In the AAV-HBV/mouse model, administration of 19f 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.

StephenW

酞嗪酮衍生物作为新型乙型肝炎病毒衣壳抑制剂的发现
陈武红1，刘菲菲2 3，赵启亮1 3，马新娜2 4，东路1，横立2 3，曾延平1 3，先贤堂2，曾立敏1，刘佳1，李阳2，建平左2 4，胡有红1 3 5
隶属关系
隶属关系

    1个
    中国科学院上海药物研究所，药物研究国家重点实验室，上海崇C路555号，中国上海201203。
    2
    中国科学院上海药物研究所免疫药理实验室，上海崇祖路555号，中国上海201203。
    3
    中国科学院大学，北京玉泉路19A号，北京100049。
    4
    上海中医药大学免疫与病毒学实验室，上海201203
    5
    杭州高等专科学校药物科学与技术学院，杭州310024

    PMID：32692159 DOI：10.1021 / acs.jmedchem.0c00346

抽象

HBV衣壳组装已被视为针对HBV的新抗病毒治疗的诱人靶标。在前导化合物4r的基础上，我们进一步研究了该目标，以鉴定具有适当抗HBV效能和改善的药代动力学（PK）特性的新型活性化合物。基于4r代谢途径的结构活性关系研究导致鉴定了具有适当抗HBV效能（体外IC50 = 0.014±0.004μM）的酞嗪酮衍生物19f，表明口服生物利用度高和肝暴露。在AAV-HBV /小鼠模型中，在以150 mg / kg的剂量每天给药两次的4周治疗期间，给予19f导致HBV DNA病毒载量减少了2.67 log。