Amino acid prodrugs of NVR3-778: Design,synthesis and anti-HBV activity |
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| Affiliation: | 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. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;1. Department of Biological Sciences, College of Natural Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, South Korea;2. Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, 06125, South Korea;3. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea;1. Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece;2. Molecular Virology Laboratory, Hellenic Pasteur Institute, 127 Vas. Sofias ave., 11521 Athens, Greece;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China;2. Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA;3. Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, USA;4. Centro de Biología Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain;1. Hepatology Unit, Hospices Civils de Lyon and Lyon University, Lyon, France;2. INSERM U1052-Cancer Research Institute of Lyon, Lyon, France;3. Janssen Pharmaceuticals NV, Beerse, Belgium;4. Spitalul Clinic Republican, ARENSIA EM, Chișinău, Moldova;5. National Institute for Infectious Diseases "Prof. Dr Matei Bals", Carol Davila University of Medicine and Pharmacy, Bucharest, Romania;6. ZNA Jan Palfijn, CPU, Antwerp, Belgium;7. Hospital Universitario Vall d''Hebrón and CIBERHED del Instituto Carlos III, Barcelona, Spain;8. Hospital Universitario Marqués de Valdecilla, IDIVAL Santander, Spain;9. Hospital Universitario Virgen del Rocio, Seville, Spain;10. Medizinische Klinik II, St. Josefs-Hospital, Weisbaden, Germany;11. Erasmus MC, University Medical Center, Rotterdam, Netherlands;12. Antwerp University Hospital, Antwerp, Belgium;13. Janssen Pharmaceuticals R&D, Titusville, New Jersey;14. Janssen Biopharma Inc., South San Francisco, California;1. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China;2. Department of Biochemistry and Molecular Biology;3. Division of Gastroenterology and Hepatology, Department of Medicine;4. Department of Pathology and Laboratory Medicine;7. Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana;5. Institute of Human Nutrition, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York;6. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana;1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana;2. Department of General Surgery, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China;3. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China;4. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York;5. Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana;6. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana |
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| 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. |
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| Keywords: | NVR3-778 Anti-HBV Prodrug Capsid assembly modulators |
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