Discovery of 4,5,6,7-Tetrahydropyrazolo[1.5-a]pyrizine Derivatives as Core Protein Allosteric Modulators (CpAMs) for the Inhibition of Hepatitis B Virus

  • J Med Chem. 2023 Oct 6. doi: 10.1021/acs.jmedchem.3c01145.
Buyu Kou  1  2 Zhisen Zhang  1  2 Xingchun Han  1  2 Zheng Zhou  2  3 Zhiheng Xu  2  3 Xue Zhou  1  4 Fang Shen  1  4 Yuan Zhou  1  4 Xiaojun Tian  1  4 Guang Yang  1  4 John A T Young  5  4 Hongxia Qiu  1  6 Giorgio Ottaviani  1  6 Alexander Mayweg  5  2 Wei Zhu  1  2 Hong C Shen  1  2 Haixia Liu  1  2 Taishan Hu  1  2
Affiliations
  • 1. China Innovation Center of Roche, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 2. Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 3. Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 4. Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 5. Roche Innovation Center Basel, Roche Pharma Research and Early Development, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 6. Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
Abstract

Hepatitis B Virus (HBV) core protein allosteric modulators (CpAMs) are an attractive class of potential anti-HBV therapeutic agents. Here we describe the efforts toward the discovery of a series of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (THPP) compounds as HBV CpAMs that effectively inhibit a broad range of nucleos(t)ide-resistant HBV variants. The lead compound 45 demonstrated inhibition of HBV DNA viral load in a HBV AAV mouse model by oral administration.

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