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

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Reddy KR, Matelich MC, Ugarkar BG, Gomez-Galeno JE, DaRe J, Ollis K, Sun Z, Craigo W, Colby TJ, Fujitaki JM, Boyer SH, van Poelje PD, Erion MD

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

J Med Chem. 2008 Feb 14;51(3):666-76. doi: 10.1021/jm7012216. Epub 2008 Jan 4.

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18173234 [ View in PubMed
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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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