2. Academic Validation
  3. Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection

Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection

  • J Med Chem. 2023 Mar 23;66(6):4253-4270. doi: 10.1021/acs.jmedchem.3c00173.
Weixing Zhang 1,  Lei Guo 1,  Haixia Liu 1,  Guolong Wu 1,  Houguang Shi 1,  Mingwei Zhou 1,  Zhisen Zhang 1,  Buyu Kou 1,  Taishan Hu 1,  Zheng Zhou 2,  Zhiheng Xu 2,  Xue Zhou 3,  Yuan Zhou 3,  Xiaojun Tian 3,  Guang Yang 3,  John A T Young 4,  Hongxia Qiu 5,  Giorgio Ottaviani 5,  Jianxun Xie 5,  Alexander V Mayweg 6,  Hong C Shen 1,  Wei Zhu 1
Affiliations

Affiliations

  • 1 China Innovation Center of Roche, Medicinal Chemistry, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 2 China Innovation Center of Roche, Lead Discovery, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 3 China Innovation Center of Roche, Discovery Virology, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 4 Roche Innovation Center Basel, Discovery Virology, Grenzacherstrasse 124, 4070 Basel, Switzerland.
  • 5 China Innovation Center of Roche, Pharmaceutical Sciences, Building 5, 371 Lishizhen Road, Shanghai 201203, China.
  • 6 Roche Innovation Center Basel, Medicinal Chemistry, Grenzacherstrasse 124, 4070 Basel, Switzerland.
PMID: 36896968 DOI: 10.1021/acs.jmedchem.3c00173
Abstract

Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV Infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients.

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