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

Apeng Wang; Shuo Wu; Zeyu Tao; Xiaoning Li; Kai Lv; Chao Ma; Yuhuan Li; Linhu Li; Mingliang Liu

doi:10.1021/acsmedchemlett.9b00184

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. eCollection 2019 Jun 13.

Authors

Apeng Wang¹, Shuo Wu^{2

3}, Zeyu Tao¹, Xiaoning Li¹, Kai Lv¹, Chao Ma¹, Yuhuan Li^{2

3}, Linhu Li¹, Mingliang Liu¹

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.

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 AUC_0-∞, 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.