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Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B.

Abstract
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.
AuthorsK Raja Reddy, Michael C Matelich, Bheemarao G Ugarkar, Jorge E Gómez-Galeno, Jay DaRe, Kristin Ollis, Zhili Sun, William Craigo, Timothy J Colby, James M Fujitaki, Serge H Boyer, Paul D van Poelje, Mark D Erion
JournalJournal of medicinal chemistry (J Med Chem) Vol. 51 Issue 3 Pg. 666-76 (Feb 14 2008) ISSN: 0022-2623 [Print] United States
PMID18173234 (Publication Type: Journal Article)
Chemical References
  • Organophosphonates
  • Organophosphorus Compounds
  • Prodrugs
  • adefovir
  • pradefovir
  • Adenine
Topics
  • Adenine (administration & dosage, analogs & derivatives, chemical synthesis, pharmacokinetics)
  • Administration, Oral
  • Animals
  • Biological Availability
  • Dogs
  • Hepatocytes (metabolism)
  • In Vitro Techniques
  • Liver (metabolism)
  • Male
  • Microsomes, Liver (metabolism)
  • Organophosphonates (administration & dosage, chemical synthesis, pharmacokinetics)
  • Organophosphorus Compounds (administration & dosage, chemical synthesis, pharmacokinetics)
  • Prodrugs
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Distribution

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