Design, Synthesis, and Anti-HBV Activity of New Bis(l-amino acid) Ester Tenofovir Prodrugs

  • ACS Med Chem Lett. 2019 May 16;10(6):991-995. doi: 10.1021/acsmedchemlett.9b00184.
Apeng Wang  1 ,  Shuo Wu  2  3 ,  Zeyu Tao  1 ,  Xiaoning Li  1 ,  Kai Lv  1 ,  Chao Ma  1 ,  Yuhuan Li  2  3 ,  Linhu Li  1 ,  Mingliang Liu  1
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2. CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 31223460 DOI: 10.1021/acsmedchemlett.9b00184
Abstract

A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 μM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 μM), a bis(l-valine) ester prodrug of TFV, was found to have obviously greater AUC0-∞, C max, and F% than tenofovir disoproxil fumarate (TDF), and potent in vivo efficacy which is not inferior to TDF in a duck HBV (DHBV) model and a HBV DNA hydrodynamic mouse model, and it may serve as a promising lead compound for further anti-HBV drug discovery.