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 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

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Tetrahydrouridine
decitabine
Cytidine Deaminase
Pharmacology
Macaca mulatta
Acids
Pharmacokinetics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. / Ferraris, Dana; Duvall, Bridget; Delahanty, Greg; Mistry, Bipin; Alt, Jesse; Rojas, Camilo; Rowbottom, Christopher; Sanders, Kristen; Schuck, Edgar; Huang, Kuan Chun; Redkar, Sanjeev; Slusher, Barbara; Tsukamoto, Takashi.

In: Journal of Medicinal Chemistry, Vol. 57, No. 6, 27.03.2014, p. 2582-2588.

Research output: Contribution to journalArticle

Ferraris, D, Duvall, B, Delahanty, G, Mistry, B, Alt, J, Rojas, C, Rowbottom, C, Sanders, K, Schuck, E, Huang, KC, Redkar, S, Slusher, B & Tsukamoto, T 2014, 'Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase', Journal of Medicinal Chemistry, vol. 57, no. 6, pp. 2582-2588. https://doi.org/10.1021/jm401856k
Ferraris, Dana ; Duvall, Bridget ; Delahanty, Greg ; Mistry, Bipin ; Alt, Jesse ; Rojas, Camilo ; Rowbottom, Christopher ; Sanders, Kristen ; Schuck, Edgar ; Huang, Kuan Chun ; Redkar, Sanjeev ; Slusher, Barbara ; Tsukamoto, Takashi. / Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 6. pp. 2582-2588.
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AU - Delahanty, Greg

AU - Mistry, Bipin

AU - Alt, Jesse

AU - Rojas, Camilo

AU - Rowbottom, Christopher

AU - Sanders, Kristen

AU - Schuck, Edgar

AU - Huang, Kuan Chun

AU - Redkar, Sanjeev

AU - Slusher, Barbara

AU - Tsukamoto, Takashi

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