Didanosine ester prodrugs: Synthesis, albumin binding properties and pharmacokinetic studies in rats

Three half-ester derivatives 10–12 of 5′-O-2′,3′-dideoxydidanosine (DDI, 1) have been synthesized. The compounds exhibited excellent correlation between partition coefficients Log P and relative in vitro bovine serum albumin binding. Using high-performance liquid chromatography–mass spectrometry (LC–MS), DDI (1) was quantitatively determined in rat plasma after intravenous injection of the azelaic acid monoester derivative (11) of DDI. The pharmacokinetic data obtained for DDI were consistent with literature. The pharmacokinetic profile of 11 showed no significant difference in AUC0–360 or curve shape compared to the parent drug DDI (1). The data indicate that the prodrug was converted to DDI within minutes after administration. High relative protein binding in vitro holds a promise for validity of the concept using more stable linker bonds.

Three monoester derivatives (10–12) of the antiviral drug 5′-O-2′,3′-dideoxydidanosine (DDI, 1) have been prepared. The half-life in rat plasma of DDI-C9 (11) has been evaluated.Figure optionsDownload as PowerPoint slide