Article ID Journal Published Year Pages File Type
1327484 Journal of Organometallic Chemistry 2005 6 Pages PDF
Abstract

Cidofovir (HPMPC, Vistide®) is a broad-spectrum anti-viral agent that is used to treat AIDS-related CMV retinitis. Currently, cidofovir is of particular interest as a potential therapy for orthopox virus infections, including smallpox. An important limitation of cidofovir and analogous nucleotide drugs in a therapeutic role is their low oral bioavailability and poor transport into cells. In principle, bioavailability of a drug can be improved by structural modification targeting transporters expressed in human intestine. To be effective, the transported prodrug must be cleaved by endogenous enzymes to its parent compound. In this work, three examples of novel cyclic cidofovir (cHPMPC) prodrugs incorporating dipeptides were synthesized and evaluated in a rat oral bioavailability model, in which the prodrugs showed significantly enhanced transport vs. HPMPC and cHPMPC. The prodrugs inhibited Gly–Sar uptake in a competitive binding assay using DC5 cells over-expressing hPepT1.

Graphical abstractCidofovir (HPMPC, Vistide®) is a broad-spectrum anti-viral agent that is used to treat AIDS-related CMV retinitis. Currently, cidofovir is of particular interest as a potential therapy for orthopox virus infections, including smallpox. An important limitation of cidofovir and analogous nucleotide drugs in a therapeutic role is their low oral bioavailability and poor transport into cells. In principle, bioavailability of a drug can be improved by structural modification targeting transporters expressed in human intestine. To be effective, the transported prodrug must be cleaved by endogenous enzymes to its parent compound. In this work, three examples of novel cyclic cidofovir (cHPMPC) prodrugs incorporating dipeptides were synthesized and evaluated in a rat oral bioavailability model, in which the prodrugs showed significantly enhanced transport vs. HPMPC and cHPMPC. The prodrugs inhibited Gly–Sar uptake in a competitive binding assay using DC5 cells over-expressing hPepT1.Figure optionsDownload full-size imageDownload as PowerPoint slide

Related Topics
Physical Sciences and Engineering Chemistry Inorganic Chemistry
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