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

Buyu Kou; Zhisen Zhang; Xingchun Han; Zheng Zhou; Zhiheng Xu; Xue Zhou; Fang Shen; Yuan Zhou; Xiaojun Tian; Guang Yang; John A T Young; Hongxia Qiu; Giorgio Ottaviani; Alexander Mayweg; Wei Zhu; Hong C Shen; Haixia Liu; Taishan Hu

doi:10.1021/acs.jmedchem.3c01145

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 26;66(20):14116-14132. doi: 10.1021/acs.jmedchem.3c01145. Epub 2023 Oct 6.

Authors

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.

PMID: 37801325
DOI: 10.1021/acs.jmedchem.3c01145

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
DNA, Viral
Hepatitis B virus
Hepatitis B* / drug therapy
Hepatitis B, Chronic* / drug therapy
Mice
Viral Core Proteins / metabolism

Substances

Antiviral Agents
Viral Core Proteins
DNA, Viral