443642-40-8Relevant articles and documents
NUCLEOSIDE DERIVATIVES AS INHIBITORS OF RNA-DEPENDENT RNA VIRAL POLYERMASE
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, (2017/07/14)
The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.
Structure - activity relationship of heterobase-modified 2′-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication
Eldrup, Anne B.,Prhavc, Marija,Brooks, Jennifer,Bhat, Balkrishen,Prakash, Thazha P.,Song, Quanlai,Bera, Sanjib,Bhat, Neelima,Dande, Prasad,Cook, P. Dan,Bennett, C. Frank,Carroll, Steven S.,Ball, Richard G.,Bosserman, Michele,Burlein, Christine,Colwell, Lawrence F.,Fay, John F.,Flores, Osvaldo A.,Getty, Krista,LaFemina, Robert L.,Leone, Joseph,MacCoss, Malcolm,McMasters, Daniel R.,Tomassini, Joanne E.,Von Langen, Derek,Wolanski, Bohdan,Olsen, David B.
, p. 5284 - 5297 (2007/10/03)
Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2′-C-methyladenosine and 2′-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2′-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2′-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2′-C-methyl ribonucleosides. The structure-activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl- β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C- methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl- β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C- methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine display improved enzymatic stability profiles as compared to that of 2′-C-methyladenosine. Consistent with these observations, the most potent compound, 4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine ribonucleoside, is orally bioavailable in the rat. Together, the potency of the 2′-C-methyl-4-amino- pyrrolo[2,3-d]pyrimidine ribonucleosides and their improved pharmacokinetic properties relative to that of 2′-C-methyladenosine suggests that this class of compounds may have clinical utility.
