Pradefovir: A Prodrug That Targets Adefovir to the Liver for the Treatment of Hepatitis B
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- 作者：K. Raja Reddy ; Michael C. Matelich ; Bheemarao G. Ugarkar ; Jorge E. Gó ; mez-Galeno ; Jay DaRe ; Kristin Ollis ; Zhili Sun ; William Craigo ; Timothy J. Colby ; James M. Fujitaki ; Serge H. Boyer ; Paul D. v
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：February 14, 2008
- 年：2008
- 卷：51
- 期：3
- 页码：666 - 676
- 全文大小：181K
- 年卷期：v.51,no.3(February 14, 2008)
- ISSN：1520-4804
文摘
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.