Development of tenofovir monobenzyl ester phosphonoamidate prodrugs with improved anti-hepatitis B virus activity and intrahepatic tenofovir enrichment

• Published in: Bioorganic & medicinal chemistry Vol. 99; p. 117607
• Main Authors: Sun, Xizheng, Song, Li, Lin, Ling, Ding, Aizhong, Wang, Chunjian, Ma, Xiaohui, Zhou, Shuiping, Cai, Jinyong, Tang, Hai
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2024; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; GS-7340; Hepatitis B; Intrahepatic TFV enrichment; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Phosphonoamidate prodrug; Physical Sciences; Science & Technology; Tenofovir; Tenofovir; Intrahepatic TFV enrichment; GS-7340; Phosphonoamidate prodrug; Hepatitis B; ACTIVATION; MECHANISM; SAFETY; RISK; BENZYL ALCOHOL; ALAFENAMIDE; ANTIVIRAL ACTIVITY; TRANSCRIPTASE INHIBITOR TENOFOVIR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2024.117607

[Display omitted] •The reported tenofovir (TFV) prodrugs have drawbacks such as low bioavailability, systemic toxicity, and relatively low intracellular conversion efficiency.•We developed a class of novel TFV monobenzyl ester phosphonoamidate prodrugs without substitutions on the benzene ring.•Two prodrugs showed excellent in vitro anti-HBV activity, in vitro stability, and in vivo TFV intrahepatic enrichment. Various tenofovir (TFV) prodrugs have been developed by introducing masking groups to the hydroxyls of the monophosphonate group to enhance intestinal absorption efficiency and therapeutic effects. However, the reported TFV prodrugs have drawbacks such as low bioavailability, systemic toxicity caused by their breakdown in non-targeted tissues, and potential low intracellular conversion efficiency. In the present study, we developed a class of TFV monobenzyl ester phosphonoamidate prodrugs without substitutions on the benzene ring. Compared with previous TFV prodrugs, compounds 3a and 3b developed in the present study showed higher anti-hepatitis B virus activity, stronger stability and higher levels of intrahepatic enrichment of the metabolic product (TFV), indicating the potential of these compounds as novel prodrugs with high efficiency and low systemic toxicity for the treatment of hepatitis B.