Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

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• 作者：Christopher McGuigan ; Karolina Madela ; Mohamed Aljarah ; Claire Bourdin ; Maria Arrica ; Emma Barrett ; Sarah Jones ; Alexander Kolykhalov ; Blair Bleiman ; K. Dawn Bryant ; Babita Ganguly ; Elena Gorovits ; Geoffrey Henson ; Damound Hunley ; Jeff Hutchins ; Jerry Muhammad ; Aleksandr Obikhod ; Joseph Patti ; C. Robin Walters ; Jin Wang ; John Vernachio ; Changalvala V. S. Ramamurty ; Srinivas K. Battina ; Stanley Chamberlain
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8632-8645
• 全文大小：590K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2鈥?C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 渭M, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases.