1029347-55-4Relevant academic research and scientific papers
Phosphoramidate ProTides of 2′-C-methylguanosine as highly potent inhibitors of hepatitis C virus. Study of their in vitro and in vivo properties
McGuigan, Christopher,Gilles, Arnaud,Madela, Karolina,Aljarah, Mohamed,Holl, Sabrina,Jones, Sarah,Vernachio, John,Hutchins, Jeff,Ames, Brenda,Bryant, K. Dawn,Gorovits, Elena,Ganguly, Babita,Hunley, Damound,Hall, Andrea,Kolykhalov, Alexander,Liu, Yule,Muhammad, Jerry,Raja, Nicholas,Walters, Robin,Wang, Jin,Chamberlain, Stanley,Henson, Geoffrey
supporting information; experimental part, p. 4949 - 4957 (2010/09/05)
Hepatitis C virus infection constitutes a serious health problem in need of more effective therapies. Nucleoside analogues with improved exposure, efficacy, and selectivity are recognized as likely key components of future HCV therapy. 2?-C-Methylguanosine triphosphate has been known as a potent inhibitor of HCV RNA polymerase for some time, but the parent nucleoside is only moderately active due to poor intracellular phosphorylation. We herein report the application of phosphoramidate ProTide technology to bypass the rate-limiting initial phosphorylation of this nucleoside. Over 30 novel ProTides are reported, with variations in the aryl, ester, and amino acid regions. l-Alanine compounds are recognized as potent and selective inhibitors of HCV in replicon assay but lack rodent plasma stability despite considerable ester variation. Amino acid variation retaining the lead benzyl ester moiety gives an increase in rodent stability but at the cost of potency. Finally l-valine esters with ester variation lead to potent, stable compounds. Pharmacokinetic studies on these agents in the mouse reveal liver exposure to the bioactive triphosphate species following single oral dosing. Systemic exposure of the ProTide and parent nucleoside are low, indicating possible low toxicity in vivo, while liver concentrations of the active species may be predictive of efficacy in the clinic. This represents one of the most thorough cross-species studies of ProTides to date.
The phosphoramidate ProTide approach greatly enhances the activity of β-2′-C-methylguanosine against hepatitis C virus
McGuigan, Christopher,Perrone, Plinio,Madela, Karolina,Neyts, Johan
experimental part, p. 4316 - 4320 (2010/06/19)
β-2′-C-Methyl purines (1, 2) are known inhibitors of hepatitis C virus (HCV). We herein report the synthesis, biological and enzymatic evaluation of their 5′-phosphoramidate ProTides. Described herein are seven l-alanine phosphoramidate derivatives with v
CHEMICAL COMPOUNDS
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Page/Page column 18-19; 26, (2008/12/05)
Phosphoramidate derivatives of nucleoside compounds derived from bases such as adenine and guanine have enhanced therapeutic potency, in particular, enhanced potency with respect to the prophylaxis or treatment of a viral infection such as hepatitis C vir
