Abstract
A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8 g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species.
MeSH terms
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Amides / chemical synthesis
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / metabolism
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Hepacivirus / drug effects
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Hepacivirus / enzymology*
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Intracellular Signaling Peptides and Proteins
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Ketones / chemical synthesis
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / metabolism
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Male
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacology
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Rats
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Rats, Wistar
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Serine Proteinase Inhibitors / chemical synthesis
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Serine Proteinase Inhibitors / metabolism
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Viral Proteins / antagonists & inhibitors*
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Viral Proteins / metabolism
Substances
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Amides
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Antiviral Agents
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Ketones
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Macrocyclic Compounds
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NS3 protein, hepatitis C virus
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NS4A cofactor peptide, Hepatitis C virus
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Protease Inhibitors
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Serine Proteinase Inhibitors
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Viral Nonstructural Proteins
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Viral Proteins