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
  • 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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