Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase
Journal of Medicinal Chemistry2014Vol. 57(6), pp. 2582–2588
Citations Over TimeTop 22% of 2014 papers
Dana Ferraris, Bridget Duvall, Greg Delahanty, Bipin Mistry, Jesse Alt, Camilo Rojas, Christopher Rowbottom, Kristen M. Sanders, Edgar Schuck, Kuan-Chun Huang, Sanjeev Redkar, Barbara Slusher, Takashi Tsukamoto
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.
Related Papers
- → An Enzymatic Assay for High-Throughput Screening of Cytidine-Producing Microbial Strains(2015)18 cited
- → Regulation of Pyrimidine Nucleotide Biosynthesis in Cytidine Deaminase-negative Mutants of Bacillus subtilis(1989)11 cited
- 2,2'-O-cyclocytidine, an antitumor cytidine analog resistant to cytidine deaminase.(1971)
- Effect of Gene knockout of cdd and thrA on Cytidine Production in E. coli(2012)
- → Cytidine Deaminase Inhibitor(2020)