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
  • 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: [email protected].
  • 6. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
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.