ABSTRACT
RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Respiratory Syncytial Virus, Human/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Biological Availability , Cell Line, Tumor , Clinical Trials as Topic , Drug Discovery , Humans , Microbial Sensitivity Tests , Protein Binding , Viral Fusion Proteins/metabolismABSTRACT
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Discovery , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/metabolism , Structure-Activity RelationshipABSTRACT
A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.
