Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 16; pp. 3707 - 3721
• Main Authors: Li, Tao, Li, Jing, Yang, Yang, Han, Yilin, Wu, Dirong, Xiao, Tao, Wang, Yang, Liu, Ting, Zhao, Yonglong, Li, Yongjun, Dai, Zeqin, Fu, Xiaozhong
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2019; Elsevier
• Subjects: Adefovir; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Hepatitis B virus; Hepatotrophic properties; Life Sciences & Biomedicine; Nephrotoxicity; Organic anion transporter 1; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Hepatotrophic properties; Adefovir; Organic anion transporter 1; Hepatitis B virus; Nephrotoxicity; TARGET; PHYSIOLOGY; HEPATITIS-B-VIRUS; ORGANIC ANION TRANSPORTERS; PATHOGENESIS; IN-VITRO EVALUATION; PRODRUGS; EXPRESSION
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.07.012

[Display omitted] The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC50 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.