title: Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.
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.
authors: Eisai Inc. , Baltimore, Maryland 21224, United States.
authors: Dana
authors: D
authors: Ferraris
authors: Bridget
authors: B
authors: Duvall
authors: Greg
authors: G
authors: Delahanty
authors: Bipin
authors: B
authors: Mistry
authors: Jesse
authors: J
authors: Alt
authors: Camilo
authors: C
authors: Rojas
authors: Christopher
authors: C
authors: Rowbottom
authors: Kristen
authors: K
authors: Sanders
authors: Edgar
authors: E
authors: Schuck
authors: Kuan-Chun
authors: KC
authors: Huang
authors: Sanjeev
authors: S
authors: Redkar
authors: Barbara B
authors: BB
authors: Slusher
authors: Takashi
authors: T
authors: Tsukamoto
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001682:Biological Availability; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials; D005461:Fluorine; D005750:Gastric Juice / Q000737:chemistry; D008253:Macaca mulatta; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013767:Tetrahydrouridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D013767:Tetrahydrouridine; D005461:Fluorine; D000077209:Decitabine; D003564:Cytidine Deaminase; D001374:Azacitidine