| Literature DB >> 18173234 |
K Raja Reddy1, 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.
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.Entities:
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Year: 2008 PMID： 18173234 DOI： 10.1021/jm7012216
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446