ABSTRACT
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Subject(s)
Biological Availability , Drug Design , Structure-Activity Relationship , Antiviral Agents/pharmacokinetics , Chemistry, Pharmaceutical , Crystallography, X-Ray , Drug Evaluation, Preclinical , Genotype , Hepacivirus/drug effects , Hepatitis C , Molecular Structure , RNA-Dependent RNA Polymerase , Viral Nonstructural Proteins/antagonists & inhibitorsABSTRACT
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Pyridones/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , Pyridones/chemical synthesis , Pyridones/pharmacology , RNA-Dependent RNA Polymerase/metabolism , Structure-Activity RelationshipABSTRACT
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyridones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Pyridones/administration & dosage , Pyridones/chemistry , Pyridones/pharmacokinetics , Structure-Activity RelationshipABSTRACT
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Chemistry, Pharmaceutical/methods , Cyclic S-Oxides/chemical synthesis , Pyridazines/chemistry , Pyridazines/chemical synthesis , Thiadiazines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/pharmacology , Caco-2 Cells , Crystallography, X-Ray/methods , Cyclic S-Oxides/pharmacology , DNA-Directed RNA Polymerases/chemistry , Drug Design , Genotype , Humans , Inhibitory Concentration 50 , Microsomes/metabolism , Models, Chemical , Molecular Conformation , Pyridazines/pharmacology , Structure-Activity Relationship , Thiadiazines/pharmacologyABSTRACT
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
