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Structure-activity Relationship of Heterobase-Modified 2'-C-methyl Ribonucleosides as Inhibitors of Hepatitis C Virus RNA Replication

Structure-activity Relationship of Heterobase-Modified 2'-C-methyl Ribonucleosides as Inhibitors of Hepatitis C Virus RNA Replication

Anne B Eldrup, Marija Prhavc, Jennifer Brooks, Balkrishen Bhat, Thazha P Prakash, Quanlai Song, Sanjib Bera, Neelima Bhat, Prasad Dande, P Dan Cook, C Frank Bennett, Steven S Carroll, Richard G Ball, Michele Bosserman, etc.

J Med Chem. 2004 Oct 7;47(21):5284-97.

PMID: 15456273

Abstract:

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-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP374750308	2′-C-Methylguanosine		374750-30-8	Price

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