期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 15, 页码 8134-8145出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00346
关键词
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资金
- 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]
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.
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