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]cytosi ne, 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 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.
Oliyai
R
R
Department of Formulation and Process Development, Gilead Sciences, Inc., 353 Lakeside Dr., Foster City, CA 94404, USA.
Lee
W A
WA
Visor
G C
GC
Yuan
L C
LC
D000998:Antiviral Agents / Q000737:chemistry*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D004355:Drug Stability; D006868:Hydrolysis; D007700:Kinetics; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C072572:cyclic-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; D003596:Cytosine; D000077404:Cidofovir