Linvencorvir
[CAS# 1808248-05-6]

Identification

• Classification: API >> Synthetic anti-infective drugs >> Antiviral drugs
• Name: Linvencorvir
• Synonyms: 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methylphenyl)-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethylpropanoic acid
• Molecular Formula: C₂₉H₃₅FN₆O₅S
• Molecular Weight: 598.69
• CAS Registry Number: 1808248-05-6
• SMILES: CCOC(=O)C1=C(NC(=N[C@H]1C2=C(C(=CC=C2)F)C)C3=NC=CS3)CN4CCN5[C@@H](C4)CN(C5=O)CC(C)(C)C(=O)O

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Linvencorvir is an investigational antiviral agent developed as a host-targeted therapy for the treatment of hepatitis B virus (HBV) infection. It functions as a small-molecule inhibitor of sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter that also serves as the primary receptor for HBV entry into hepatocytes. By blocking viral entry at the host cell surface, linvencorvir offers a novel approach to HBV therapy that is distinct from conventional nucleos(t)ide analogues, which primarily act by inhibiting viral replication after infection has occurred.

Linvencorvir was developed with the aim of preventing the establishment and spread of HBV infection in the liver. NTCP was identified as a functional receptor for HBV and hepatitis delta virus (HDV), and this discovery opened new avenues for therapeutic intervention targeting viral entry. Linvencorvir competitively inhibits the binding of HBV preS1 protein to NTCP, thereby blocking the first step of viral infection. This mechanism also impairs HBV cell-to-cell spread, which plays a role in the maintenance and persistence of chronic HBV infection.

The development of linvencorvir addresses an unmet need in HBV treatment, particularly in light of the limitations of current therapies. While nucleos(t)ide analogues effectively suppress viral replication and reduce liver inflammation, they do not eliminate covalently closed circular DNA (cccDNA), which serves as a persistent reservoir for viral replication. Entry inhibitors like linvencorvir do not affect cccDNA directly but are believed to contribute to its eventual reduction by preventing new rounds of infection and hepatocyte reinfection.

In preclinical studies, linvencorvir demonstrated potent and selective inhibition of HBV entry in hepatoma cell lines expressing NTCP. It showed minimal effects on bile acid transport at therapeutic concentrations, indicating a favorable selectivity profile. In animal models, linvencorvir effectively prevented HBV infection and was well tolerated without evidence of hepatotoxicity. These findings supported its progression to clinical development.

Linvencorvir has been evaluated in early-phase clinical trials for safety, pharmacokinetics, and antiviral activity in both healthy volunteers and patients with chronic HBV infection. The compound was found to be orally bioavailable and generally well tolerated. In infected individuals, treatment with linvencorvir resulted in reductions in HBV DNA and hepatitis B surface antigen (HBsAg) levels, consistent with its mechanism of blocking new infections and reducing viral load over time. Some studies have explored linvencorvir in combination with nucleos(t)ide analogues to assess potential additive or synergistic effects.

Beyond HBV, linvencorvir may have potential application in the treatment of HDV, which requires HBV co-infection for replication. Since HDV entry into hepatocytes also depends on NTCP, linvencorvir’s ability to block this receptor could inhibit both viruses simultaneously. This dual-action potential makes it a promising candidate for broader antiviral strategies targeting viral hepatitis.

Linvencorvir’s development aligns with the broader strategy of achieving a functional cure for HBV, defined as sustained loss of HBsAg with or without seroconversion. While monotherapy with entry inhibitors may not be sufficient to achieve this goal, their use in combination with other antiviral agents and immune modulators is being actively investigated. Linvencorvir represents a first-in-class NTCP-targeted therapy, contributing a new mechanism to the HBV treatment arsenal.

The compound’s tolerability, oral formulation, and novel mechanism make it a strong candidate for continued development. If successful in later-stage trials, linvencorvir could become a key component of combination therapies aimed at controlling or curing chronic HBV infection, potentially transforming long-term disease management and reducing the global burden of hepatitis B.

References

2023. Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection. Journal of Medicinal Chemistry, 66(6).
DOI: 10.1021/acs.jmedchem.3c00173

2024. Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients. Clinical and Molecular Hepatology, 30(2).
DOI: 10.3350/cmh.2023.0422

2024. Linvencorvir: Paving the way for functional cure in hepatitis B. Clinical and Molecular Hepatology, 30(2).
DOI: 10.3350/cmh.2024.0149