2. Academic Validation
  3. Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity

Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity

  • Bioorg Med Chem Lett. 2020 May 1;30(9):127103. doi: 10.1016/j.bmcl.2020.127103.
Kai Lv 1,  Wenyan Li 2,  Shuo Wu 1,  Yunhe Geng 3,  Apeng Wang 1,  Lu Yang 1,  Menghao Huang 4,  Kushan Chowdhury 4,  Yuhuan Li 5,  Mingliang Liu 6
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; College of Chemistry & Material Science, Hebei Normal University, Shijiazhuang 050024, China.
  • 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: yuhuanlibj@126.com.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: lmllyx@126.com.
PMID: 32173194 DOI: 10.1016/j.bmcl.2020.127103
Abstract

A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.

Keywords

Anti-HBV; Capsid assembly modulators; NVR3-778; Prodrug.

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