title: Synthesis, biotransformation, pharmacokinetics, and antiviral properties of 5-ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers.
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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Cheraghali
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001711:Biotransformation; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015774:Ganciclovir / Q000494:pharmacology; D008297:Male; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014498:Uracil / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000998:Antiviral Agents; C087238:5-bromo-5-ethyl-6-methoxy-5,6-dihydro-2'-deoxyuridine; C087239:5-chloro-5-ethyl-6-methoxy-5,6-dihydro-2'-deoxyuridine; C022811:edoxudin; C048011:5-ethyluracil; D014498:Uracil; D015774:Ganciclovir; D003857:Deoxyuridine