ABSTRACT
The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, â¼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.
Subject(s)
Anti-Bacterial Agents/pharmacology , Boronic Acids/pharmacology , Carbapenem-Resistant Enterobacteriaceae/drug effects , Enterobacteriaceae Infections/drug therapy , Meropenem/pharmacology , Bacterial Proteins/metabolism , Enterobacteriaceae Infections/metabolism , Humans , Microbial Sensitivity Tests/methodsABSTRACT
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
Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.
Subject(s)
Aerosols/administration & dosage , Anti-Bacterial Agents/therapeutic use , Levofloxacin , Lung Diseases/drug therapy , Ofloxacin/therapeutic use , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/physiology , Administration, Inhalation , Animals , Anti-Bacterial Agents/administration & dosage , Aztreonam/administration & dosage , Aztreonam/pharmacokinetics , Aztreonam/therapeutic use , Disease Models, Animal , Female , Lung Diseases/microbiology , Mice , Microbial Sensitivity Tests , Ofloxacin/administration & dosage , Ofloxacin/pharmacokinetics , Pseudomonas Infections/microbiology , Tobramycin/administration & dosage , Tobramycin/pharmacokinetics , Tobramycin/therapeutic useABSTRACT
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
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Microsomes, Liver/drug effects , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Humans , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
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).
Subject(s)
Chemistry, Pharmaceutical/methods , Hepacivirus/enzymology , Microsomes, Liver/enzymology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Thiazines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Caco-2 Cells , Crystallography, X-Ray/methods , Drug Design , Hepacivirus/drug effects , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Pyridazines/chemistry , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacology , Time FactorsABSTRACT
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
Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa approximately non-basic-8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Thrombin/antagonists & inhibitors , Animals , Area Under Curve , Biological Availability , Bridged Bicyclo Compounds/pharmacokinetics , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Indicators and Reagents , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Investigations on P(2)-P(3)-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P(1)-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P(1)-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines.