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Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors.

Boloor, Amogh; Hanway, Denise; Joshi, Maria; Winn, David T; Mendez, Gabriel; Walls, Marlena; Wei, Ping; Qian, Fuxin; Zhang, Xiaoli; Zhang, Yuliang; Hepperle, Michael E; Li, Xinqiang; Campbell, David A; Betancort, Juan M.

Bioorg Med Chem Lett ; 19(19): 5708-11, 2009 Oct 01.

Article in English | MEDLINE | ID: mdl-19713109

ABSTRACT

A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.

Subject(s)

Antiviral Agents/chemical synthesis , Boronic Acids/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Hepacivirus/drug effects , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Boronic Acids/chemistry , Boronic Acids/pharmacology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line, Tumor , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Humans , Intracellular Signaling Peptides and Proteins , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism

ABSTRACT

Subject(s)

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