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.
Subject(s)
Cytidine Deaminase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Tetrahydrouridine/analogs & derivatives , Tetrahydrouridine/chemical synthesis , Animals , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Biological Availability , Decitabine , Drug Design , Drug Stability , Enzyme Inhibitors/pharmacokinetics , Excitatory Postsynaptic Potentials , Fluorine , Gastric Juice/chemistry , Macaca mulatta , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Tetrahydrouridine/pharmacologyABSTRACT
The alpha-hydroxyamido functionality of 2'-deoxytetrahydrouridine (dTHU) makes this seemingly simple and generally useful compound difficult to obtain. Reported synthetic strategies produce extremely poor yields and multiple products, and full characterization data is not available. Described herein is a two-step approach for synthesizing dTHU in increased yields and purity; stability concerns are also addressed. Catalytic reduction (5% Rh/alumina) of 2'-deoxyuridine, followed by reduction with sodium borohydride as a limiting reagent, produces dTHU and limits formation of side products. Evidence was obtained for formation of a methoxy-substituted analogue during purification. By this strategy, dTHU of >95% purity can be obtained in 40% yield on a 150 mg scale.
