Application of Phosphoramidate ProTide Technology Significantly Improves Antiviral Potency of Carbocyclic Adenosine Derivatives

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• 作者：Christopher McGuigan ; Alshaimaa Hassan-Abdallah ; Sheila Srinivasan ; Yikang Wang ; Adam Siddiqui ; Susan M. Daluge ; Kristjan S. Gudmundsson ; Huiqiang Zhou ; Ed W. McLean ; Jennifer P. Peckham ; Thimysta C.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 30, 2006
• 年：2006
• 卷：49
• 期：24
• 页码：7215 - 7226
• 全文大小：170K
• 年卷期：v.49,no.24(November 30, 2006)
• ISSN：1520-4804

文摘

We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agentcarbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared byGrignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improvedanti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regionsof the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinctSARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4Aand the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potencyimprovements over the parent drug. In conclusion, the ProTide approach is highly successful when appliedto L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinicalcandidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinalS9 fractions.