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
The Aurora kinases are a group of serine/threonine protein kinases that regulate key steps during mitosis, and deregulation of these proteins (e.g., by gene amplification or overexpression) has been linked to a wide variety of tumor types. Thus, Aurora-A and Aurora-B have been intensely studied as targets for anticancer therapy and are now clinically validated targets. Here we report on the development of a novel fluorescence intensity binding assay for Aurora-A kinase inhibitors using a fluorescently labeled probe compound that shows intramolecular quenching when unbound but exhibits a dramatic increase in fluorescence when bound to Aurora-A.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Spectrometry, Fluorescence/methods , Aurora Kinase B , Aurora Kinases , Binding, Competitive/drug effects , Cell Line , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Ligands , Protein Binding/drug effects , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolismABSTRACT
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Amides/blood , Amides/chemistry , Amino Acids/genetics , Amino Acids/metabolism , Binding Sites , Biphenyl Compounds/blood , Biphenyl Compounds/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Lipopolysaccharides/pharmacology , Molecular Conformation , Molecular Structure , Naphthalenes/pharmacology , Pyrazoles/pharmacology , Structure-Activity RelationshipABSTRACT
The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Amides/chemistry , Amides/pharmacokinetics , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/metabolism , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Oxadiazoles/chemistry , Oxadiazoles/pharmacokinetics , Oxadiazoles/pharmacology , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistry , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The biphenyl amides (BPAs) are a novel series of p38 MAP kinase inhibitors. The discovery of the series through structure-based focused screening is described, and the binding mode of the compounds is explained with reference to X-ray crystal structures.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/chemistry , Amides/metabolism , Biphenyl Compounds/chemistry , Biphenyl Compounds/metabolism , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/chemistry , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.
Subject(s)
Enzyme Inhibitors/pharmacology , Indazoles/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Enzyme Inhibitors/pharmacokinetics , Indazoles/pharmacokinetics , Models, MolecularABSTRACT
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.
