2-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Abstract

6-Methoxypurine arabinoside [9-(β-D-arabinofuranosyl)-6-methoxy-9H-purine; 1] is a potent and selective agent against varicella-zoster virus in vitro. Studies in the rat indicated that extensive first pass metabolism of this nucleoside occurred after oral dosing, presumably from high levels of adenosine deaminase in the intestine. Only 3.8% of an oral dose of 6-methoxypurine arabinoside was recovered in the urine. In an attempt to improve these unfavourable pharmacokinetics, a series of twenty-five 2′-esters of 6-methoxypurine arabinoside were prepared either by direct acylation or by a protection, acylation, and deprotection sequence. These esters were evaluated in the rat for their suitability as prodrugs on the basis of urinary recovery of 1 after oral dosing. The straight-chain aliphatic esters, but not the branched chain or aromatic esters, improved this urinary recovery. The 2′-valerate, hexanoate, heptanoate, and octanoate esters (2d–g, respectively) were the most effective, with urinary recoveries of 1 above 15%. The water solubility of the valerate ester was high (107 mM at 37°C and pH 7.2), but solubilities progressively decreased with the longer chain esters. The combination of high water solubility and improved metabolic stability upon oral dosing made 2d the prodrug of choice for both oral and intravenous dosing.