Design, synthesis, and anti-HIV activity of 4′-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors

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• 作者：Constantine G. Boojamra ; Jay P. Parrish ; David Sper ; io ; Ying Gao ; Oleg V. Petrakovsky ; Sharon K. Lee ; David Y. Markevitch ; Jennifer E. Vela ; Genevieve Laflamme ; James M. Chen ; Adrian S. Ray ; Abraham C
• 关键词：Antiviral ; Antiviral therapy ; Reverse transcriptase ; Reverse-transcriptase inhibitors ; Nucleosides ; Nucleotides ; Phosphorylation ; Diphosphophosphonate ; HIV treatment ; Carbocyclic nucleosides
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：15 February 2009
• 年：2009
• 卷：17
• 期：4
• 页码：1739-1746
• 全文大小：481 K

文摘

A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC₅₀ = 0.13 μM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC₅₀ = 16 μM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.