Susceptibility of recent clinical isolates of herpes simplex virus to 5-ethyl-2'-deoxyuridine: preferential inhibition of herpes simplex virus type 2

Teh, C. Z.; Sacks, Stephen L.

doi:10.1128/aac.23.5.637

Cited by 18 publications

(3 citation statements)

References 17 publications

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“…1) is a selective antiherpetic agent that is phosphorylated by herpes simplex virus-encoded thymidine kinase (HSV-TK), but not by mammalian TK (Bernaerts and De Clercq, 1987). EDU has antiviral activity against several strains of HSV (De Clercq and Shugar, 1975;Teh and Sacks, 1983) and is an effective, non-mutagenic antiviral agent for the treatment of topical HSV infections (Swierkowski and Shugar, 1969). It has been reported to increase the survival time of mice with HSV encephalitis (HSE) (Davis et al, 1979) but it is not approved for this use clinically.…”

Section: Dedicationmentioning

confidence: 97%

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Cheraghali

Kumar

Morin

et al. 1995

Antivir Chem Chemother

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(+)- Trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5′-O-valeryl-2′-deoxyuridine (3) and (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-3′,5′-di-O-valery[-2′-deoxyuridine (4) were synthesized in 55% and 8.6% yield, respectively, by esterification of the 5′-hydroxyl group of (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-2′-deoxyuridine (2) using valeryl chloride. [4-14C]-3 and [4-14C]-4 were synthesized in 79% and 64% chemical and radiochemical yield, respectively, by similar esterifications of [4-14C]-2. The double prodrug 3 was readily hydrolysed (> 95% in 8 min) to 5-ethyl-2′-deoxyuridine (EDU) by porcine liver esterase in vitro. The biotransformations of 2 and 3 were studied following i.v. injection of a 0.4 mmol/kg i.v. dose to male Balb/c mice. The single prodrug 2 was rapidly cleared (<10 min) from the blood. The area under the blood concentration-time curve (AUC) for EDU, as a metabolite of 2, was higher (2.1 ± 0.4 μmol.h.g−1) than the AUC observed when EDU itself was injected (1.7 ± 0.2 μmol.h.g−1). The double prodrug 3 provided a sustained high concentration of EDU in blood, with an AUC for EDU, as a metabolite of 3, of 1.8 ± 0.2 μmol.hr.g−1. 5′-O-Valeryl-5-ethyl-2′-deoxyuridine and 3 were both detected in blood samples collected up to 35 min post i.v. injection. 5-Ethyluracil and 5-(1-hydroxyethyl)-uracil were identified as secondary metabolites of EDU, 2 and 3. Compared to [4-14C]-EDU, i.v. injection of [4-14C]-3 or [4-14C]-4 provided significantly higher (P < 0.001) radioactivity levels in the brain, but neither EDU, 2 or 3 protected mice against intracerebral herpes simplex virus infection. Hepatic uptakes of 2, 3 and 4, in mice, were similar to each other despite the respective substantial increases in both molecular weight and lipophilicity of this series. In rats, biliary excretion over the 0-4 h period after i.v. injection accounted for only 2.9-3.9% of the injected dose for these prodrugs.

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Section: Dedicationmentioning

confidence: 97%

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Cheraghali

Kumar

Morin

et al. 1995

Antivir Chem Chemother

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“…Filtration and removal of solvent in vacuo afforded a pale yellow solid, which was recrystallized from cyclohexane-ethyl acetate. This provided the hydroxynaphthalenone 3b as white needles (1.56 g, 71%): mp 122-122.5 °C; IR (KBr) 3300 (OH), 1685 cm-1 (0=0); NMR (CDC13) 1.59 (s, 3 H, C (6) or C(7) methyl), 1.66 (s, 3 H, C (6) or C(7) methyl), 1.91 (s, 1 H, exchange with D20), 1.88-2.28 (m, material 3b remained as shown by gas chromatography. Removal of benzene under reduced pressure afforded a yellow oil, which was purified by silica gel column chromatography (1:1 ethyl acetate-petroleum ether).…”

mentioning

confidence: 99%

Synthesis and antiviral activity of 11-azapentacyclo[6.2.1.0.2,70.4,1005,9]decane

Sacks¹,

Scheffer²,

Teh³

et al. 1985

J. Med. Chem.

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11-Azapentacyclo[6.2.1.0.0.0]decane (6a) as well as its 6,7-dimethyl derivative 6b was synthesized by a novel, four-step sequence that holds promise for the construction of a variety of cage compounds with bridging nitrogen atoms. The hydrochloride salt of 6a was shown to possess no antiviral activity against either the influenza virus A/Victoria/3/75 or the herpes simplex viruses HSV-1 and HSV-2.

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“…In vitro testing by reduction in cytopathic effect has identified the mean 50% inhibitory dose against HSV type 1 (HSV-1) and HSV type 2 (HSV-2) to be 0.3 to 0.5 FLg/ml in primary rabbit kidney cells (8) and BHK-21 cells (22). In vivo, EdU has shown efficacy in the rabbit model of HSV keratitis (17) and has been used in Europe for human herpes keratitis (11).…”

mentioning

confidence: 99%

Comparison of topically applied 5-ethyl-2'-deoxyuridine and acyclovir in the treatment of cutaneous herpes simplex virus infection in guinea pigs

Spruance¹,

Freeman²,

Sheth³

1985

Antimicrob Agents Chemother

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Three percent 5-ethyl-2'-deoxyuridine (EdU) in an aqueous cream base was compared with 5% acyclovir (ACV) in polyethylene glycol ointment and 3% EdU in 95% dimethyl sulfoxide (DMSO) for efficacy in the topical treatment of an experimental dorsal cutaneous herpes simplex virus type 1 infection in guinea pigs. Topical ACV treatment reduced the mean lesion number by 15%, the lesion area by 32%, and the lesion virus titer by 60% when compared with measurements at contralateral sites treated with the vehicle alone. Application of 3% EdU cream was more beneficial, effecting reductions of 29, 44, and 68% in the same measurements. EdU in DMSO was even more effective, reducing the lesion measurements by 39, 60, and 90%, respectively. The penetration of EdU and ACV through guinea pig skin was compared in single-chamber diffusion cells. In the aqueous cream, EdU readily penetrated excised skin and exhibited rates of flux 10-fold greater than those shown by ACV in ointment formnulation (0.56 versus 0.05 pg/cm2 per h; P = 0.05). The flux of EdU in DMSO was 3.39 jig/cm2 per h, six times higher than the flux in the cream vehicle. EdU was more effective than ACV in this experimental animal model, most likely due to better percutaneous drug delivery of EdU from the cream and DMSO vehicles.The activity of 5-ethyl-2'-deoxyuridine (EdU) against infection with herpes simplex virus (HSV) was first recognized in 1967 (13). In vitro testing by reduction in cytopathic effect has identified the mean 50% inhibitory dose against HSV type 1 (HSV-1) and HSV type 2 (HSV-2) to be 0.3 to 0.5

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Susceptibility of recent clinical isolates of herpes simplex virus to 5-ethyl-2'-deoxyuridine: preferential inhibition of herpes simplex virus type 2

Abstract: We examined the in vitro susceptibilities of three reference strains and 41 recent clinical isolates of herpes simplex virus types 1 and 2 to 5-ethyl-2'-deoxyuridine. This thymidine analog exerts a type 2-preferential

Cited by 18 publications

References 17 publications

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs

Synthesis and antiviral activity of 11-azapentacyclo[6.2.1.0.2,70.4,1005,9]decane

Comparison of topically applied 5-ethyl-2'-deoxyuridine and acyclovir in the treatment of cutaneous herpes simplex virus infection in guinea pigs

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