Design, Synthesis, and Pharmacological Evaluation of Fluorinated Tetrahydrouridine Derivatives as Inhibitors of Cytidine Deaminase

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2582-2588
• 全文大小：374K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Several 2鈥?fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2鈥?Deoxy-2鈥?2鈥?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.