SYNTHESIS, BIOTRANSFORMATION, AND PHARMACOKINETIC STUDIES OF 9-(BETA-D-ARABINOFURANOSYL)-6-AZIDOPURINE - A PRODRUG FOR ARA-A DESIGNED TO UTILIZE THE AZIDE REDUCTION PATHWAY

As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(beta-4-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformatio n pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in v ivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homoge nates. The half-lives of 6-AAP in serum and liver and brain homogenate s were 3.73, 4.90, and 7.29 h, respectively. 6-AAP was metabolized pri marily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6-AAP was fou nd to be stable to adenosine deaminase in a separate in vitro study. T he in vivo metabolism and disposition of ara-A and 6-AAP were conducte d in mice. When 6-AAP was administered by either oral or intravenous r oute, the half-life of ara-A was 7-14 times higher than for ara-A admi nistered intravenously. Ara-A could not be found in the brain after th e intravenous administration of ara-A. However, after 6-AAP administra tion (by either oral or intravenous route), significant levels of ara- A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide redu ction approach on other clinically useful agents containing an amino g roup are in progress in our laboratories.