Pradefovir: A Prodrug That Targets Adefovir to the Liver for the Treatment of Hepatitis B

Reddy, K. Rajender; Matelich, Michael C.; Ugarkar, Bheemarao G.; Gómez-Galeno, Jorge; DaRe, Jay; Ollis, Kristin; Sun, Zhili; Craigo, William A.; Colby, Timothy J.; Fujitaki, James M.; Boyer, Serge H.; Poelje, Paul D. van; Erion, Mark D.

doi:10.1021/jm7012216

Cited by 65 publications

(40 citation statements)

References 34 publications

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“…LMV and ADV have liver/serum ratios of 0.007 and 0.38, respectively (Reddy et al, 2008). Liver/serum ratios for TDF and ETV could not be found in the literature.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro

Bader

Korba

2010

Antiviral Research

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Statins are 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors used for the treatment of hypercholesterolemia. We report that a particular statin, simvastatin (SIM), exhibits strong in vitro anti-HBV activity. Moreover, a combination of SIM with each of the individual nucleos(t)ide analogues lamivudine (LMV), adefovir (ADV), tenofovir (TEN) and entecavir (ETV), showed synergistic antiviral activity. Combination drug treatments were performed in the HepG2.2.15 cell line. Compound combinations were centered on a mixture designed to deliver approximately equipotent (not necessarily equimolar) concentrations of each agent, based on the ninety percent viral inhibition monotherapy values. SIM interacted favorably with all four licensed anti-HBV nucleos(t)ide analogues, especially at molar ratios that approximate combinations likely to be used clinically. As the relative concentration of SIM was raised to an excess, the overall favorability of the interactions progressively increased.SIM displayed about equal degrees of synergy with ADV and TDF. The highest degree of synergy was observed at the 300:1 combination of SIM with ETV. Interactions with LMV were the least favorable. The in vitro potential shown here may greatly augment anti-HBV therapy clinically.

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“…LMV and ADV have liver/serum ratios of 0.007 and 0.38, respectively (Reddy et al, 2008). Liver/serum ratios for TDF and ETV could not be found in the literature.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro

Bader

Korba

2010

Antiviral Research

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“…Dexamethasone glucuronide thus showed low potential for absorption in the upper gastrointestinal tract of rats, and hydrolyzable by the gut flora. A good example is provided by pradefovir (5.54), a prodrug currently in clinical trials as the cis-(2R,4S)-isomer shown here [85]. The drug was bound to a high-molecular dextran via a succinate linker, with the conjugate containing about one drug molecule for ca.…”

Section: Fig 525mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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“…On the other hand, pradefovir mesylate, a propylated adefovir that depends upon CYP3A mediated activation, looked promising in Phase 2 studies, but was put on hold because of tumor formation in animals (Reddy et al, 2008). The development of MIV210 (Michalak et al, 2009) has also been abandoned (Grogan, 2013).…”

Section: Direct-acting Antiviralsmentioning

confidence: 99%

Chronic hepatitis B: A wave of new therapies on the horizon

2015

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This year marks the 50th anniversary of the discovery of the Australia antigen (Blumberg, Alter and Visnich, 1965), which in 1968 was identified to be the hepatitis B virus (HBV) surface antigen. Even though several antiviral medications have been in use for the management of chronic HBV infection for more than 20 years, sustained clearance of HBsAg, similar to the sustained viral response (SVR) or cure in chronic hepatitis C (HCV), occurs in only a minority of treated patients. Moreover, even after 10 years of effective suppression of HBV viremia with current therapy, there is only a 40-70% reduction in deaths from liver cancer. Recent success in developing antivirals for hepatitis C that are effective across all genotypes has renewed interest in a similar cure for chronic HBV infection. In this article, we review a wave of newly identified drug targets, investigational compounds and experimental strategies that are now under clinical evaluation or in preclinical development. The paper forms part of a symposium in Antiviral Research on “An unfinished story: From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”

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Pradefovir: A Prodrug That Targets Adefovir to the Liver for the Treatment of Hepatitis B

Cited by 65 publications

References 34 publications

Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro

Simvastatin potentiates the anti-hepatitis B virus activity of FDA-approved nucleoside analogue inhibitors in vitro

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Chronic hepatitis B: A wave of new therapies on the horizon

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