2. Academic Validation
  3. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase

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.
Dana Ferraris 1,  Bridget Duvall,  Greg Delahanty,  Bipin Mistry,  Jesse Alt,  Camilo Rojas,  Christopher Rowbottom,  Kristen Sanders,  Edgar Schuck,  Kuan-Chun Huang,  Sanjeev Redkar,  Barbara B Slusher,  Takashi Tsukamoto
Affiliations

Affiliation

  • 1 Eisai Inc. , Baltimore, Maryland 21224, United States.
PMID: 24520856 DOI: 10.1021/jm401856k
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.

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