Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase

Dana Ferraris, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2582-2588
Number of pages7
JournalJournal of medicinal chemistry
Volume57
Issue number6
DOIs
StatePublished - Mar 27 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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