ABSTRACT
Chronic hepatitis C virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of new treatment options. We recently disclosed 1H-benzo[de]isoquinoline-1,3(2H)-diones as allosteric inhibitors of NS5B Polymerase. Structural and SAR information guided us in the modification of the core structure leading to new templates with improved activity and toxicity/activity window.
Subject(s)
Antiviral Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Allosteric Regulation , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Conformation , Protein Structure, Tertiary , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.
Subject(s)
Antiviral Agents/chemical synthesis , Isoquinolines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Drug Resistance, Viral , Genotype , Hepacivirus/genetics , Hepacivirus/physiology , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Molecular Structure , Mutation , Rats , Replicon/drug effects , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Virus ReplicationABSTRACT
Thieno[3,2-b]pyrroles are a novel class of allosteric inhibitors of HCV NS5B RNA-dependent RNA polymerase which show potent affinity for the NS5B enzyme. Introduction of a polar substituent in the position N1 led to a compound that efficiently blocks subgenomic HCV RNA replication in HUH-7 cells with an EC50 of 2.9 microM.