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.
- 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.
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.