Di- and triester prodrugs of the varicella-zoster antiviral agent 6-methoxypurine arabinoside

• Published in: Journal of medicinal chemistry Vol. 35; no. 1; pp. 56 - 63
• Main Authors: Jones, Lynda A, Moorman, Allan R, Chamberlain, Stanley D, De Miranda, Paulo, Reynolds, David J, Burns, Charlene L, Krenitsky, Thomas A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.01.1992
• Subjects: Administration, Oral; Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Arabinonucleosides - chemical synthesis; Arabinonucleosides - chemistry; Arabinonucleosides - pharmacokinetics; Biological Availability; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Male; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00079a006

6-Methoxypurine arabinoside (9-beta-D-arabinofuranosyl-6-methoxy-9H-purine, 1) has potent and selective activity against varicella-zoster virus in vitro. An unfavourable metabolic profile observed with oral dosing in the rat led to the preparation of a variety of 2',3',5'-triesters (2a-n) and several 2',3'-, 2',5'-, and 3',5'-diesters of this arabinoside (3a-n, 4a-f, and 5a-j, respectively). The compounds were evaluated as prodrugs by measuring the urinary levels of 1 in rat urine after oral dosing. With the exception of triacetate 2a, the triesters failed to significantly enhance bioavailability. Administration of compound 2a resulted in a 3-fold increase in systemic availability of 1, possibly because of its increased water solubility (1.6 times more soluble than 1) and only slightly increased relative log P value (1.93 vs 0.50 for 1). The longer chain aliphatic triesters and aromatic triesters had lower water solubilities and increased lipophilic partitioning. These factors might account for the lower systemic bioavailability of these compounds. In contrast, the diesters, especially the aliphatic diesters, showed significantly improved systemic availability. This might be a consequence of the higher aqueous solubilities and enhanced partition coefficients seen with these compounds. 2',3'-Diacetate 3a showed the best combination of high systemic availability and water solubility of all the prodrugs of 1.