2',3'-Dideoxy-2'-fluoro-ara-a. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV)

Márquez, Víctor E.; Tseng, Christopher K. H.; Kelley, James A.; Mitsuya, Hiroaki; Broder, Samuel; Roth, Julius A.; Driscoll, John S.

doi:10.1016/0006-2952(87)90254-1

Cited by 113 publications

(60 citation statements)

References 7 publications

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“…Recently, several fluorinated nucleoside analogs have been reported as inhibitors of HIV-1 (10,11,13,14,19,25). However, modification with fluorine was not always advantageous but depended on the position of the fluorine and the combination of fluorination with other modifications of the pentose ring.…”

Section: Resultsmentioning

confidence: 99%

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Koshida

Cox

Harmenberg

et al. 1989

Antimicrob Agents Chemother

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One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

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Section: Resultsmentioning

confidence: 99%

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Koshida

Cox

Harmenberg

et al. 1989

Antimicrob Agents Chemother

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“…3 -6 High-performance liquid chromatographic/ultraviolet (HPLC/UV) methods have been developed to determine F-ddA and F-ddI levels in the biological fluids of rat, monkey and human. The limit of quantitation for parent drug and metabolite in human plasma using this technique is 50 ng ml 1 and the HPLC analysis requires 35 min per sample. 7,8 Owing to the low levels of F-ddA relative to F-ddI measured in biological fluids, a more sensitive method is needed to permit the detection of the parent drug over a longer time course and so define better its overall plasma pharmacokinetics.…”

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confidence: 99%

“…1 The addition of an electrophilic fluorine in the 2 0 -position of the dideoxyribose ring ( Fig. 1) yields a compound that is acid stable and is approximately ten times more resistant to hydrolysis by adenosine deaminase (ADA) than is ddA.…”

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confidence: 99%

Determination of lodenosine and its major metabolite in human plasma by liquid chromatography/electrospray ionization tandem mass spectrometry

2000

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A sensitive and selective method for the determination of 2'-beta-fluoro-2',3'-dideoxyadenosine (lodenosine, F-ddA), an experimental anti-AIDS drug, and its major metabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), in human plasma was developed and validated. The procedure employs two internal standards and a simple ultrafiltration step followed by chromatography on a Betasil C(18) minibore column. An in-line valve is used to remove salts before reaching the ion source. Detection is by electrospray ionization tandem mass spectrometry with selected reaction monitoring. The method has a limit of quantitation of 4 ng ml(-1) (16 nM) for F-ddA and 8 ng ml(-1) (32 nM) for F-ddI with a linear range up to 2000 ng ml(-1) (7.9 microM) for each. Predicted concentrations from a three-day validation study were within 5% of the nominal values for F-ddA and 16% for F-ddI. Intra- and inter-assay precision, as measured by relative standard deviation, was 13% or better for both compounds. To achieve good reproducibility, many variables related to the electrospray ionization were optimized for both precision and sensitivity. The method was successfully employed to analyze samples and evaluate plasma pharmacokinetics from a Phase I clinical trial.

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“…Its anti-HIV active deamination product, 2Ј-␤-fluoro-2Ј,3Ј-dideoxyinosine (F-ddI), is equally acid-stable and is a purine nucleoside phosphorylase (PNP)-resistant isostere of ddI. The improved lipophilicity (10 times more lipophilic than F-ddI) (Barchi et al, 1991), acid stability, and reduced deamination rate of F-ddA, coupled with the PNP resistance of its deamination product, made this compound a candidate for oral formulation, which is considered to be the most practical route for chronic anti-AIDS therapy in a large patient population (Marquez et al, 1987.…”

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confidence: 99%

Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug

Johnson

Chen²,

Anderson³

2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:Enhanced central nervous system (CNS) delivery of certain poorly penetrating 2,3-dideoxynucleosides has been achieved by designing prodrugs that are substrates for enzymes, such as adenosine deaminase (ADA), that are present at high activities in brain tissue. In this study, the potential role of adenosine deaminase localized within the endothelial cells of the blood-brain barrier (BBB) in providing enhanced intracellular and CNS delivery of an ADA-activated prodrug is assessed in vitro using cell culture models of the BBB. The kinetics of uptake and bioconversion of 2-␤-fluoro-2,3-dideoxyadenosine (F-ddA), a model ADA-activated prodrug of 2-␤-fluoro-2,3-dideoxyinosine, were determined in primary cultured bovine brain microvascular endothelial cells. Model-based simulations of CNS availability derived from in vitro estimates of parameters for simple passive diffusion and ADAcatalyzed deamination suggest that ADA that is localized within the BBB plays an important role in the conversion of F-ddA to 2-␤-fluoro-2,3-dideoxyinosine during its passage across the BBB. Consistent with in vivo observations, these simulations demonstrate that elevated levels of certain enzymes, such as ADA, in the brain microvascular endothelial cells of the BBB may be exploited in the design of brain-targeted prodrugs or drug-carrier conjugates, which brain tissue selectively converts.

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2',3'-Dideoxy-2'-fluoro-ara-a. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV)

Cited by 113 publications

References 7 publications

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Determination of lodenosine and its major metabolite in human plasma by liquid chromatography/electrospray ionization tandem mass spectrometry

Investigation of the Mechanism of Enhancement of Central Nervous System Delivery of 2′-β-Fluoro-2′,3′-Dideoxyinosine Via a Blood-Brain Barrier Adenosine Deaminase-Activated Prodrug

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