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
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Thiazoles/chemical synthesis , Thiophenes/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Genotype , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , RNA, Viral/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiophenes/pharmacokineticsABSTRACT
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).
Subject(s)
Antiviral Agents/pharmacology , Pyridazines/pharmacology , Pyrroles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Binding Sites/drug effects , Cell Line , Crystallography, X-Ray , Humans , Hydrogen Bonding , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Hepacivirus/drug effects , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/blood , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Microsomes, Liver/drug effects , Molecular Structure , Pyridazines/blood , Pyridazines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Hepacivirus/enzymology , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Drug Design , Haplorhini , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
Translation inhibitors of the 3,5-diamino-piperidine series act as aminoglycoside mimetics that inhibit bacterial growth. Here we show antibacterial SAR in the presence and absence of serum with a particular focus toward Pseudomonas aeruginosa.
Subject(s)
Aminoglycosides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Protein Biosynthesis/drug effects , Pseudomonas aeruginosa/drug effects , Animals , Anti-Bacterial Agents/blood , Combinatorial Chemistry Techniques , Diamines/blood , Escherichia coli/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , Piperidines/blood , Structure-Activity RelationshipABSTRACT
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure-activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed.
Subject(s)
Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/metabolism , Crystallography, X-Ray , Drug Design , Drug Stability , Enzyme Inhibitors/metabolism , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Models, Molecular , Pyridazines/metabolism , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.
