1. Synthesis, transport and antiviral activity of Ala–Ser and Val–Ser prodrugs of cidofovir
- Author
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Boris A. Kashemirov, Jae-Seung Kim, Paul Kijek, Kathy Borysko, John M. Hilfinger, Stefanie Mitchell, Larryn W. Peterson, John C. Drach, Charles E. McKenna, and Julie M. Breitenbach
- Subjects
Stereochemistry ,Clinical Biochemistry ,Organophosphonates ,Administration, Oral ,Cytomegalovirus ,Pharmaceutical Science ,Pharmacology ,Antiviral Agents ,Biochemistry ,Chemical synthesis ,Article ,Cytosine ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Oral administration ,Valine ,Drug Discovery ,Serine ,Animals ,Humans ,Prodrugs ,Molecular Biology ,Cells, Cultured ,Alanine ,Dipeptide ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Biological activity ,Prodrug ,In vitro ,Rats ,Disease Models, Animal ,chemistry ,Molecular Medicine ,Peptides ,Cidofovir - Abstract
We report the synthesis and biological evaluation of Ala-(Val-)l-Ser-CO(2)R prodrugs of 1, where a dipeptide promoiety is conjugated to the P(OH)(2) group of cidofovir (1) via esterification by the Ser side chain hydroxyl group and an ethyl group (4 and 5) or alone (6 and 7). In a murine model, oral administration of 4 or 5 did not significantly increase total cidofovir species in the plasma compared to 1 or 2, but 7 resulted in a 15-fold increase in a rat model and had an in vitro EC(50) value against human cytomegalovirus comparable to 1. Neither 6 nor 7 exhibited toxicity up to 100 μM in KB or HFF cells.
- Published
- 2011
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