Document Detail


2-(3-Thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acids as inhibitors of HCV NS5B RdRp.
MedLine Citation:
PMID:  19800789     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of 2-(3-thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acid inhibitors of the hepatitis C virus (HCV) NS5B polymerase enzyme are reported. Sulfonyl urea substituted analogs in this series proved to be the most potent active site non-nucleoside inhibitors of NS5B reported to date. These compounds had low nanomolar enzyme inhibition across HCV genotypes 1-3 and showed single digit micromolar inhibition in the HCV replicon assay. This improved cell-based activity allowed the binding mode of these compounds to be probed by selection of resistant mutations against compound 21. The results generated are in broad agreement with the previously proposed binding model for this compound class.
Authors:
Barbara Pacini; Salvatore Avolio; Caterina Ercolani; Uwe Koch; Giovanni Migliaccio; Frank Narjes; Laura Pacini; Licia Tomei; Steven Harper
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Publication Detail:
Type:  Journal Article     Date:  2009-07-17
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  19     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-12     Completed Date:  2010-01-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  6245-9     Citation Subset:  IM    
Affiliation:
IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, 00040 Pomezia, Rome, Italy. barbara_pacini@merck.com
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MeSH Terms
Descriptor/Qualifier:
Antiviral Agents / chemical synthesis,  chemistry*,  pharmacology
Carboxylic Acids / chemical synthesis,  chemistry*,  pharmacology
Catalytic Domain
Cell Line, Tumor
Computer Simulation
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology
Hepacivirus / enzymology*
Humans
RNA Replicase / antagonists & inhibitors*,  metabolism
Structure-Activity Relationship
Viral Nonstructural Proteins / metabolism*
Virus Replication / drug effects,  genetics
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/Carboxylic Acids; 0/Enzyme Inhibitors; 0/NS-5 protein, hepatitis C virus; 0/Viral Nonstructural Proteins; EC 2.7.7.48/RNA Replicase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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