Abstract
Introduction of various modified prolines at P(2) and optimization of the P(1) side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K(i)*= 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC(50) and IC(90) of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.
MeSH terms
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Amides / chemistry*
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Amides / pharmacology*
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Animals
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Genome, Viral / genetics*
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Haplorhini
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Models, Molecular
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Molecular Structure
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Oligopeptides / chemistry*
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Oligopeptides / pharmacology*
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RNA, Viral / genetics
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Rats
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / metabolism*
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology
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Viral Nonstructural Proteins / chemistry
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Viral Nonstructural Proteins / metabolism
Substances
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Amides
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NS3 protein, hepatitis C virus
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Oligopeptides
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RNA, Viral
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SCH6
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Serine Endopeptidases