Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.
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Ferraris D, Duvall B, Delahanty G, Mistry B, Alt J, Rojas C, Rowbottom C, Sanders K, Schuck E, Huang KC, Redkar S, Slusher BB, Tsukamoto T
Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.
J Med Chem. 2014 Mar 27;57(6):2582-8. doi: 10.1021/jm401856k. Epub 2014 Feb 24.
- PubMed ID
- 24520856 [ View in PubMed]
- Abstract
Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Cedazuridine Cytidine deaminase Protein Humans YesInhibitorDetails - Drug Reactions
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