Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors

doi:10.1021/acs.jmedchem.0c00346

	Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
	Chen, Wuhong 3; Liu, Feifei 1,4; Zhao, Qiliang 3,4; Ma, Xinna 1,2; Lu, Dong 3; Li, Heng 1,4; Zeng, Yanping 3,4; Tong, Xiankun 1; Zeng, Limin 3; Liu, Jia 3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-08-13
卷号	63 期号:15 页码:8134-8145
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.0c00346
通讯作者	Yang, Li(yangli@simm.ac.cn) ; Zuo, Jianping(jpzuo@simm.ac.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81872725] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; National Science Foundation of Shanghai[17ZR1436400] ; National Science and Technology Major Project[2018ZX09711002-014-004]
WOS关键词	REPLICATION ; DESIGN ; ANALOGS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000562941200013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292430]
专题	中国科学院上海药物研究所
通讯作者	Yang, Li; Zuo, Jianping; Hu, Youhong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Immunopharmacol, Shanghai 201203, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Lab Immunol & Virol, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式 GB/T 7714	Chen, Wuhong,Liu, Feifei,Zhao, Qiliang,et al. Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(15):8134-8145.
APA	Chen, Wuhong.,Liu, Feifei.,Zhao, Qiliang.,Ma, Xinna.,Lu, Dong.,...&Hu, Youhong.(2020).Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,63(15),8134-8145.
MLA	Chen, Wuhong,et al."Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 63.15(2020):8134-8145.