2. Academic Validation
  3. Discovery of (1 H-Pyrazolo[3,4- c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

Discovery of (1 H-Pyrazolo[3,4- c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint

  • J Med Chem. 2020 Jun 11;63(11):6066-6089. doi: 10.1021/acs.jmedchem.0c00292.
Chunting Wang 1,  Yameng Pei 1 2,  Lin Wang 3,  Shuo Li 4,  Chao Jiang 4,  Xu Tan 4,  Yi Dong 5,  Ye Xiang 6,  Yao Ma 5,  Gang Liu 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 2 Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 4 Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 5 Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 6 Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Center for Global Health and Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
PMID: 32421339 DOI: 10.1021/acs.jmedchem.0c00292
Abstract

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV Infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV Infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.

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