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

(+)-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.