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.
Department of Formulation and Process Development, Gilead Sciences, Inc., 353 Lakeside Dr., Foster City, CA 94404, USA.
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Oliyai
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Lee
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Visor
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Yuan
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