SYNTHESIS, BIOTRANSFORMATION, PHARMACOKINETICS, AND ANTIVIRAL PROPERTIES OF ETHYL-5-HALO-6-METHOXY-5,6-DIHYDRO-2'-DEOXYURIDINE DIASTEREOMERS

Diastereomers of ethyl-5-halo-6-methoxy-5,6-dihydro-2'-deoxyuridine we re synthesized by the regiospecific addition of XOMe (X = Br, Cl) to t he 5,6-olefinic bond of 5-ethyl-2'-deoxyuridine (EDU). 5-(1-Hydroxyeth yl)-2'-deoxyuridine (HEDU) was identified asa metabolite of the romo-5 -ethyl-6-methoxy-5,6-dihydro-2'-deoxyuridine diastereomers (BMEDU). Th e concentration of EDU and 5-ethyluracil (EU) in blood was higher afte r i.v. administration of the bromo diastereomers (BMEDU) to rats, rela tive to the concentration of EDU and EU after injection of the chloro (CMEDU) diastereomers. The CMEDU diastereomers were found to be oxidiz ed less extensively to HEDU, were more stable to glycosidic bond cleav age, and were converted more slowly to EDU, than the BMEDU compounds. These BMEDU and CMEDU diastereomers exhibited pharmacokinetics charact erized by a biphasic decline in plasma concentration. All diastereomer s exhibited a characteristic second maximum blood concentration (C-max ), which was attributed to reabsorption after biliary excretion. All o f these 5-ethyl-5-halo-6-methoxy-5,6-dihydro compounds, with the excep tion of (5S,6S)-BMEDU, had higher AUC values (ranging from 0.32 to 1.2 0 mu M.hr.mL(-1)) and lower plasma clearances (10-36 mL.min(-1)) relat ive to the AUC values (0.14 mu M.hr.mL(-1)) and plasma clearance (85 m L.min(-1)) of EDU. These BMEDU and CMEDU diastereomers are more lipoph ilic (log P = -0.42 to 0.40 range) than EDU (log P = -1.09), which sho uld enhance their ability to cross the blood-brain barrier. These 5,6- dihydro compounds showed higher levels (11-22%) of binding to bovine s erum albumin than EDU (7%). The BMEDU compounds exhibited equipotent i n vitro antiviral activity to EDU against HSV-1 and HSV-2, whereas the CMEDU analogs were inactive. The (5S,6R)-CMEDU diastereomer was equip otent to ganciclovir in the human cytomegalovirus assay.