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.
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Authors | K 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 51
Issue 3
Pg. 666-76
(Feb 14 2008)
ISSN: 0022-2623 [Print] United States |
PMID | 18173234
(Publication Type: Journal Article)
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Chemical References |
- Organophosphonates
- Organophosphorus Compounds
- Prodrugs
- adefovir
- pradefovir
- Adenine
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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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