2. Academic Validation
  3. Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors

Discovery of Phthalazinone Derivatives as Novel Hepatitis B Virus Capsid Inhibitors

  • J Med Chem. 2020 Aug 13;63(15):8134-8145. doi: 10.1021/acs.jmedchem.0c00346.
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.

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