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

被引：62

作者：

Reddy, K. Raja ^{[1
]}

Matelich, Michael C. ^{[1
]}

Ugarkar, Bheemarao G. ^{[1
]}

Gomez-Galeno, Jorge E. ^{[1
]}

DaRe, Jay ^{[1
]}

Ollis, Kristin ^{[1
]}

Sun, Zhili ^{[1
]}

Craigo, William ^{[1
]}

Colby, Timothy J. ^{[2
]}

Fujitaki, James M. ^{[2
]}

Boyer, Serge H. ^{[1
]}

van Poelje, Paul D. ^{[2
]}

Erion, Mark D. ^{[1
,2
]}

机构：

[1] Metabasis Therapeut Inc, Dept Chem, La Jolla, CA 92037 USA

[2] Metabasis Therapeut Inc, Dept Biochem, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 03期

关键词：

D O I：

10.1021/jm7012216

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：666 / 676

页数：11

共 40 条

[1] HIGH-YIELD PREPARATION OF ISOLATED RAT LIVER PARENCHYMAL CELLS - A BIOCHEMICAL AND FINE STRUCTURAL STUDY [J].

BERRY, MN ;

FRIEND, DS .

JOURNAL OF CELL BIOLOGY, 1969, 43 (03) :506-+

[2] Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-β-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma [J].

Boyer, Serge H. ;

Sun, Zhili ;

Jiang, Hongjian ;

Esterbrook, Julie ;

Gomez-Galeno, Jorge E. ;

Craigo, William ;

Reddy, K. Raja ;

Ugarkar, Bheemarao G. ;

MacKenna, Deidre A. ;

Erion, Mark D. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (26) :7711-7720

[3] USE OF CARBOHYDRATE-DERIVATIVES FOR STUDIES OF PHOSPHORUS STEREOCHEMISTRY .2. SYNTHESIS AND CONFIGURATIONAL ASSIGNMENTS OF 1,-3,2-OXATHIAPHOSPHORINAN-2-ONES AND 1,3,2-DIOXAPHOSPHORINAN-2-THIONES [J].

COOPER, DB ;

HARRISON, JM ;

INCH, TD ;

LEWIS, GJ .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1974, (10) :1049-1052

[4] LEWIS ACID MEDIATED CONDENSATION OF ALKENOLS AND ALDEHYDES - A SELECTIVE SYNTHESIS OF TETRAHYDROPYRANS AND OXEPANES [J].

COPPI, L ;

RICCI, A ;

TADDEI, M .

JOURNAL OF ORGANIC CHEMISTRY, 1988, 53 (04) :911-913

[5]

Erion MD, 2006, CURR OPIN INVESTIG D, V7, P109

[6] Liver-targeted drug delivery using HepDirect1 prodrugs [J].

Erion, MD ;

van Poelje, PD ;

MacKenna, DA ;

Colby, TJ ;

Montag, AC ;

Fujitaki, JM ;

Linemeyer, DL ;

Bullough, DA .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 312 (02) :554-560

[7] 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 [J].

Erion, MD ;

Reddy, KR ;

Boyer, SH ;

Matelich, MC ;

Gornez-Galeno, J ;

Lemus, RH ;

Ugarkar, BG ;

Colby, TJ ;

Schanzer, J ;

van Poelje, PD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (16) :5154-5163

[8]

FREEMAN S, 1997, PROGR MED CHEM, V34, P111

[9] INTRACELLULAR COMPARTMENTATION AND CONTROL OF ALANINE METABOLISM IN RAT-LIVER PARENCHYMAL-CELLS [J].

GROEN, AK ;

SIPS, HJ ;

VERVOORN, RC ;

TAGER, JM .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1982, 122 (01) :87-93

[10]

Hadziyannis S, 2005, HEPATOLOGY, V42, p754A

← 1 2 3 4 →