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Title: Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
Authors: McGuigan, Christopher ×
Hassan-Abdallah, Alshaimaa
Srinivasan, Sheila
Wang, Yikang
Siddiqui, Adam
Daluge, Susan M
Gudmundsson, Kristjan S
Zhou, Huiqiang
McLean, Ed W
Peckham, Jennifer P
Burnette, Thimysta C
Marr, Harry
Hazen, Richard
Condreay, Lynn D
Johnson, Lance
Balzarini, Jan #
Issue Date: Nov-2006
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:49 issue:24 pages:7215-7226
Abstract: We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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