Pradefovir: A Prodrug That Targets Adefovir to the Liver for the Treatment of Hepatitis B

• Published in: Journal of medicinal chemistry Vol. 51; no. 3; pp. 666 - 676
• Main Authors: Reddy, K. Raja, Matelich, Michael C, Ugarkar, Bheemarao G, Gómez-Galeno, Jorge E, DaRe, Jay, Ollis, Kristin, Sun, Zhili, Craigo, William, Colby, Timothy J, Fujitaki, James M, Boyer, Serge H, van Poelje, Paul D, Erion, Mark D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.02.2008; Amer Chemical Soc
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - pharmacokinetics; Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Dogs; Hepatocytes - metabolism; In Vitro Techniques; Life Sciences & Biomedicine; Liver - metabolism; Male; Medical sciences; Microsomes, Liver - metabolism; Organophosphonates - administration & dosage; Organophosphonates - chemical synthesis; Organophosphonates - pharmacokinetics; Organophosphorus Compounds - administration & dosage; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - pharmacokinetics; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution; LAMIVUDINE; HEPDIRECT PRODRUGS; THERAPY; PHOSPHONATES; PHARMACOKINETICS; METABOLISM; MONOPHOSPHATE; PARENCHYMAL-CELLS; DIPIVOXIL; PMEA; RNA-directed DNA polymerase; Rat; Liver; Orthohepadnavirus; Hepatic disease; Phosphorus Organic compounds; Kidney; Hepatitis; Tissue; Hepadnaviridae; Reverse transcriptase inhibitor; Antiviral; Hepatitis B virus; Chemical synthesis; Purine nucleotide; Acyclic nucleotide; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Organic phosphonate; Bioavailability; Prodrug; Pradefovir; Virus; Nucleotidyltransferases; Vertebrata; Adefovir; Mammalia; Treatment; Animal; Distribution; Digestive diseases; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm7012216

Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.