| Structure-activity relationship of heterobase-modified 2'-C-methyl ribonucleosides as inhibitors of hepatitis C virus RNA replication. | |
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MedLine Citation:
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PMID: 15456273 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Christine Burlein; Lawrence F Colwell; John F Fay; Osvaldo A Flores; Krista Getty; Robert L LaFemina; Joseph Leone; Malcolm MacCoss; Daniel R McMasters; Joanne E Tomassini; Derek Von Langen; Bohdan Wolanski; David B Olsen |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 47 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-09-30 Completed Date: 2004-11-10 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 5284-97 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, Isis Pharmaceuticals, 2280 Faraday Avenue, Carlsbad, CA 92008, USA. aeldrup@isisph.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Deaminase
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chemistry Administration, Oral Animals Antiviral Agents / chemical synthesis*, chemistry, pharmacokinetics Biological Availability Cell Line Drug Stability Hepacivirus / genetics* Models, Molecular Molecular Conformation Molecular Structure Phosphorylation Purine-Nucleoside Phosphorylase / chemistry RNA, Viral / antagonists & inhibitors*, biosynthesis Rats Ribonucleosides / chemical synthesis*, chemistry, pharmacokinetics Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/4-amino-5-fluoro-7H-pyrrolo(2,3-d)pyrimidine ribonucleoside; 0/Antiviral Agents; 0/RNA, Viral; 0/Ribonucleosides; EC 2.4.2.1/Purine-Nucleoside Phosphorylase; EC 3.5.4.4/Adenosine Deaminase |
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