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 degrees C. cHPMPC manifested greater chemical stability than cidofovir, except und er alkaline conditions (pH > 9). Three degradation products-cidofovir, cycl ic 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 ra te constants for cHPMPC under acidic conditions were derived from the degra dation product curves. The deamination rate constants fbr cHPMPC were about 8-fold slower compared to that for cidofovir. The enhanced chemical stabil ity for cHPMPC relative to cidofovir is attributed to the absence of intram olecular catalysis with cHPMPC. (C) 1999 Elsevier Science B.V. All rights r eserved.