Enhanced chemical stability of the intracellular prodrug, 1-[(( S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, relative to its parent compound, cidofovir

Degradation kinetics of cyclic HPMPC (cHPMPC), 1-[(( S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, and its parent compound cidofovir (also known as HPMPC) were conducted in the pH range of 2–11 at 70°C. cHPMPC manifested greater chemical stability than cidofovir, except under alkaline conditions (pH>9). Three degradation products—cidofovir, cyclic HPMPU and HPMPU—were identified for cHPMPC, and the product distribution was characterized via a stability-indicating HPLC assay. Cyclic HPMPU and HPMPU are the uracil analogs of cHPMPC and cidofovir, respectively, formed through a hydrolytic deamination pathway. The deamination and hydrolysis rate constants for cHPMPC under acidic conditions were derived from the degradation product curves. The deamination rate constants for cHPMPC were about 8-fold slower compared to that for cidofovir. The enhanced chemical stability for cHPMPC relative to cidofovir is attributed to the absence of intramolecular catalysis with cHPMPC.