Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors
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–...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-08, Vol.63 (15), p.8134-8145 |
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| container_issue | 15 |
| container_start_page | 8134 |
| container_title | Journal of medicinal chemistry |
| container_volume | 63 |
| creator | Chen, Wuhong Liu, Feifei Zhao, Qiliang Ma, Xinna Lu, Dong Li, Heng Zeng, Yanping Tong, Xiankun Zeng, Limin Liu, Jia Yang, Li Zuo, Jianping Hu, Youhong |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00346 |
| format | Article |
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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. 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Med. Chem</addtitle><description>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. 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Med. Chem</addtitle><date>2020-08-13</date><risdate>2020</risdate><volume>63</volume><issue>15</issue><spage>8134</spage><epage>8145</epage><pages>8134-8145</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.jmedchem.0c00346</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-1770-6272</orcidid></addata></record> |
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| source | ACS Publications |
| title | Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors |
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