Synthesis, biotransformation, pharmacokinetics, and antiviral properties of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers.

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Cheraghali AM, Kumar R, Wang L, Knaus EE, Wiebe LI

Synthesis, biotransformation, pharmacokinetics, and antiviral properties of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers.

Biochem Pharmacol. 1994 Apr 29;47(9):1615-25.

PubMed ID

8185676 [ View in PubMed

]

Abstract

Diastereomers of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine were synthesized by the regiospecific addition of XOMe (X = Br, Cl) to the 5,6-olefinic bond of 5-ethyl-2'-deoxyuridine (EDU). 5-(1-Hydroxyethyl)-2'-deoxyuridine (HEDU) was identified as a metabolite of the 5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers (BMEDU). The concentration of EDU and 5-ethyluracil (EU) in blood was higher after i.v. administration of the bromo diastereomers (BMEDU) to rats, relative to the concentration of EDU and EU after injection of the chloro (CMEDU) diastereomers. The CMEDU diastereomers were found to be oxidized less extensively to HEDU, were more stable to glycosidic bond cleavage, and were converted more slowly to EDU, than the BMEDU compounds. These BMEDU and CMEDU diastereomers exhibited pharmacokinetics characterized by a biphasic decline in plasma concentration. All diastereomers exhibited a characteristic second maximum blood concentration (Cmax), which was attributed to reabsorption after biliary excretion. All of these 5-ethyl-5-halo-6-methoxy-5,6-dihydro compounds, with the exception of (5S,6S)-BMEDU, had higher AUC values (ranging from 0.32 to 1.20 microM.hr.mL-1) and lower plasma clearances (10-36 mL.min-1) relative to the AUC values (0.14 microM.hr.mL-1) and plasma clearance (85 mL.min-1) of EDU. These BMEDU and CMEDU diastereomers are more lipophilic (log P = -0.42 to 0.40 range) than EDU (log P = -1.09), which should enhance their ability to cross the blood-brain barrier. These 5,6-dihydro compounds showed higher levels (11-22%) of binding to bovine serum albumin than EDU (7%). The BMEDU compounds exhibited equipotent in vitro antiviral activity to EDU against HSV-1 and HSV-2, whereas the CMEDU analogs were inactive. The (5S,6R)-CMEDU diastereomer was equipotent to ganciclovir in the human cytomegalovirus assay.

DrugBank Data that Cites this Article

Drugs

Edoxudine

Drug Carriers

Drug	Carrier	Kind	Organism	Pharmacological Action	Actions
Edoxudine	Serum albumin	Protein	Humans	No	Binder	Details