Design, Synthesis, and Characterization of a Series of Cytochrome P450 3A-Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting Phosph(on)ate-Based Drugs to the Liver
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- 作者：Mark D. Erion ; K. Raja Reddy ; Serge H. Boyer ; Michael C. Matelich ; Jorge Gomez-Galeno ; Robert H. Lemus ; Bheemarao G. Ugarkar ; Timothy J. Colby ; Jü ; rgen Schanzer ; and Paul D. van Poelje
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：April 28, 2004
- 年：2004
- 卷：126
- 期：16
- 页码：5154 - 5163
- 全文大小：149K
- 年卷期：v.126,no.16(April 28, 2004)
- ISSN：1520-5126
文摘
A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, is describedthat combines properties of rapid liver cleavage with high plasma and tissue stability to achieve increaseddrug levels in the liver. The prodrugs are substituted cyclic 1,3-propanyl esters designed to undergo anoxidative cleavage reaction catalyzed by a cytochrome P450 (CYP) expressed predominantly in the liver.Reported herein is the discovery of a prodrug series containing an aryl substituent at C4 and its use for thedelivery of nucleoside-based drugs to the liver. Prodrugs of 5'-monophosphates of vidarabine, lamivudine(3TC), and cytarabine as well as the phosphonic acid adefovir were shown to cleave following exposureto liver homogenates and exhibit good stability in blood and other tissues. Prodrug cleavage required thepresence of the aryl group in the cis-configuration, but was relatively independent of the nucleoside andabsolute stereochemistry at C4. Mechanistic studies suggested that prodrug cleavage proceeded via aninitial CYP3A-catalyzed oxidation to an intermediate ring-opened monoacid, which subsequently wasconverted to the phosph(on)ate and an aryl vinyl ketone by a 
ddle">-elimination reaction. Studies in primary rathepatocytes and normal rats comparing 3TC and the corresponding HepDirect prodrug demonstrated theability of these prodrugs to effectively bypass the rate-limiting nucleoside kinase step and produce higherlevels of the biologically active nucleoside triphosphate.
ddle">-elimination reaction. Studies in primary rathepatocytes and normal rats comparing 3TC and the corresponding HepDirect prodrug demonstrated theability of these prodrugs to effectively bypass the rate-limiting nucleoside kinase step and produce higherlevels of the biologically active nucleoside triphosphate.