Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine

Chu, C. K.; Bhadti, V. S.; Doshi, K. J.; Etse, Joseph T.; Gallo, James M.; Boudinot, F. Douglas; Schinazi, R. F.

doi:10.1021/jm00170a023

Cited by 89 publications

(31 citation statements)

References 8 publications

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“…Steady-state prodrug concentrations were not significantly different in CSF and brain tissue, whereas the ddl concentrations in brain tissue were nearly twofold higher than those in CSF at steady-state because of an apparent slower rate of efflux of ddl from brain tissue. (mm) tIn- (mm) k., (min-') khyd (mm-) (g-min/ml) (>g. min/ml) (ml/mi/kg) system initially developed by Bodor et al (5), but the degrees of enhancement of delivery of AZT to CNS that have been reported are highly variable from laboratory to laboratory (7,10,20,21). Recent findings that a series of lipophilic 6-halo-ddPs exhibit activity against HIV in vitro (11,18,35,36) and that their activities were completely abrogated in the presence of an ADA inhibitor (23,35,36) coupled with preliminary indications of enhanced CNS delivery via this approach in rats (2), suggest a promising new enzyme-based strategy for improving the delivery of dideoxynucleosides to the CNS.…”

Section: Resultsmentioning

confidence: 99%

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Morgan

Murakami

et al. 1992

Antimicrob Agents Chemother

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AIDS dementia complex is a neurologic disorder, characterized by increasingly severe cognitive, behavioral, and motor impairment, which is associated with human immunodeficiency virus (HIV) infection in the central nervous system (CNS). Many of the dideoxynucleosides effective systemically in the treatment of HlIV infections, such as 2',3'-dideoxyinosine (ddI), exhibit limited penetration into the CNS and limited or variable effectiveness in reversing the symptoms of AIDS dementia. Thus, approaches for increasing the CNS uptake of ddI and other dideoxynucleosides are needed. The CNS uptake of a series of 6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddPs) previously shown to be active against HIV because of their conversion to ddl through the action of adenosine deaminase was examined in rats. In vitro studies in rat blood and brain tissue homogenate suggested a favorable selectivity for bioconversion in brain tissue, but with bioconversion half-lives varying widely within the series. In vivo infusions of 6-chloro-ddP (6-CI-ddP), 6-bromo-ddP (6-Br-ddP), and 6-iodo-ddP (6-I-ddP) resulted in significant increases (20-to 34-fold) in the ddI concentration ratios in brain parenchyma/plasma when compared with those after an infusion of ddI alone. Absolute concentrations of ddI in brain parenchyma were increased 10-and 4-fold, respectively, following 30-min infusions of 6-Cl-ddP or 6-Br-ddP, but were 2.4-fold lower after an infusion of 6-I-ddP relative to that after a control infusion of ddM. Detailed studies of the plasma pharmacokinetics, CNS uptake kinetics, and bioconversion of 6-Cl-ddP were conducted to compare in vivo transport and bioconversion parameters with those predicted from in vitro measurements and to rationalize the efficiency of CNS delivery of ddI from 6-Cl-ddP. The results show that increased lipophilicity alone does not ensure that a given prodrug will deliver higher levels of a parent compound to the CNS. Both the selectivity and absolute rate of bioconversion in the brain are important factors.

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Section: Resultsmentioning

confidence: 99%

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Morgan

Murakami

et al. 1992

Antimicrob Agents Chemother

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“…While a variety of targetors have been examined, derivatives of the dihydronicotinate-nicotinate redox couple have proven to be the most successful. Application of the approach to a number of drugs, including antiviral nucleosides, has been reported (1,4,7,9,10,24,25).…”

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confidence: 99%

Enhanced delivery of ganciclovir to the brain through the use of redox targeting

Brewster

Raghavan

Pop

et al. 1994

Antimicrob Agents Chemother

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Enhanced delivery of ganciclovir to the brain was demonstrated by a redox-based chemical delivery system. A ganciclovir monoester in which a 1-methyl-1,4-dihydronicotinate was covalently attached to one of the hydroxymethyl functions was prepared. The stability of the ganciclovir chemical delivery system (DHPG-CDS) was evaluated in aqueous buffers and organ homogenates. In vivo distribution studies in the rat indicated that while ganciclovir poorly penetrated into the central nervous system and was rapidly eliminated, DHPG-CDS provided for therapeutically relevant (2.7 ,uM) and sustained levels of the parent compound through 6 h. An analysis of the area under the concentration curve indicated that the chemical delivery system delivered five times more ganciclovir than that of the parent drug. The high levels in the brain and reduced levels in the blood gave a brain-to-blood drug concentration ratio of 2.54 for ganciclovir when delivered by the chemical delivery system, compared to a ratio of 0.063 when the parent drug was administered. These data suggest that DHPG-CDS could be a useful adjunct for the treatment of cytomegalovirus encephalitis.

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“…As part of these efforts, we have synthesized and studied dihydropyridine derivatives (Bodor et al, 1981) of AZT and 3'-azido-2',3'-dideoxyuridine (AZdU) (Chu et al, 1990a). In vivo studies in mice indicated that the dihydropyridine derivatives significantly enhanced the delivery of the parent nucleosides to the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Chemicals 6-Chloro-2' ,3'-dideoxypurine (6-CI-ddP), 2',3'-dideoxyinosine (ddl), 6-chloro-purine base (6-CI-purine) and 3'-azido-2',3'-dideoxyuridine (AZdU) were synthesized as previously described (Chu et al, 1990a). The chemical purity of the compounds, confirmed by spectral and high-performance liquid chromatographic (HPLC) analysis, was greater than 98%.…”

Section: Materials and Experimental Proceduresmentioning

confidence: 99%

Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

Doshi

Boudinot

Gallo

et al. 1994

Antivir Chem Chemother

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Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.

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Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine

Cited by 89 publications

References 8 publications

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs

Enhanced delivery of ganciclovir to the brain through the use of redox targeting

Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

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