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Your search keyword '"Bardelle C"' showing total 5 results
Start Over Author "Bardelle C" Journal bioorganic medicinal chemistry letters
5 results on '"Bardelle C"'

1. The discovery of benzanilides as c-Met receptor tyrosine kinase inhibitors by a directed screening approach.

Author

Allen JV, Bardelle C, Blades K, Buttar D, Chapman L, Colclough N, Dossetter AG, Garner AP, Girdwood A, Lambert C, Leach AG, Law B, Major J, Plant H, and Slater AM

Subjects
Anilides chemical synthesis, Anilides chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-met metabolism, Stereoisomerism, Structure-Activity Relationship, Anilides pharmacology, Drug Discovery, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors
Abstract

A directed screen of a relatively small number of compounds, selected for kinase ATP pocket binding potential, yielded a novel series of hit compounds (1). Hit explosion on two binding residues identified compounds 27 and 43 as the best leads for an optimization program having reduced secondary metabolism, as measured by in vitro rat hepatocytes incubation, leading to oral bio-availability. Structure-activity relationships and molecular modeling have suggested a binding mode for the most potent inhibitor 12., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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2. Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series.

Author

Barlaam B, Ducray R, Lambert-van der Brempt C, Plé P, Bardelle C, Brooks N, Coleman T, Cross D, Kettle JG, and Read J

Subjects
Administration, Oral, Aniline Compounds chemical synthesis, Aniline Compounds pharmacokinetics, Animals, Benzyl Alcohol chemical synthesis, Benzyl Alcohol pharmacokinetics, Binding Sites, Computer Simulation, Crystallography, X-Ray, Drug Evaluation, Preclinical, Mice, Mice, Nude, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Receptor, EphB4 metabolism, Structure-Activity Relationship, Aniline Compounds chemistry, Benzyl Alcohol chemistry, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Receptor, EphB4 antagonists & inhibitors
Abstract

Optimization of our bis-anilino-pyrimidine series of EphB4 kinase inhibitors led to the discovery of compound 12 which incorporates a key m-hydroxymethylene group on the C4 aniline. 12 displays a good kinase selectivity profile, good physical properties and pharmacokinetic parameters, suggesting it is a suitable candidate to investigate the therapeutic potential of EphB4 kinase inhibitors., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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3. Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non-benzodioxole-based kinase inhibitors.

Author

Bardelle C, Barlaam B, Brooks N, Coleman T, Cross D, Ducray R, Green I, Brempt CL, Olivier A, and Read J

Subjects
Animals, Benzodioxoles pharmacokinetics, CHO Cells, Cricetinae, Cricetulus, Crystallography, X-Ray, Dogs, Female, Male, Mice, Mice, Nude, Models, Molecular, Phosphorylation, Protein Kinase Inhibitors pharmacokinetics, Rats, Rats, Wistar, Structure-Activity Relationship, Substrate Specificity, src-Family Kinases antagonists & inhibitors, Benzodioxoles chemical synthesis, Benzodioxoles pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Receptor, EphB4 antagonists & inhibitors
Abstract

Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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4. Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines.

Author

Bardelle C, Coleman T, Cross D, Davenport S, Kettle JG, Ko EJ, Leach AG, Mortlock A, Read J, Roberts NJ, Robins P, and Williams EJ

Subjects
Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Receptor, EphB4 antagonists & inhibitors
Abstract

Crystallographic studies of a range of 3-substituted anilinopyrimidine inhibitors of EphB4 have highlighted two alternative C-2 aniline conformations and this discovery has been exploited in the design of a highly potent series of 3,5-disubstituted anilinopyrimidines. The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics.

Published
2008
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5. Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines.

Author

Bardelle C, Cross D, Davenport S, Kettle JG, Ko EJ, Leach AG, Mortlock A, Read J, Roberts NJ, Robins P, and Williams EJ

Subjects
Aniline Compounds chemical synthesis, Hydrogen Bonding, Isomerism, Models, Chemical, Protein Kinase Inhibitors chemical synthesis, Pyrimidines chemical synthesis, Structure-Activity Relationship, Aniline Compounds pharmacology, Drug Design, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Receptor, EphB4 antagonists & inhibitors
Abstract

A series of bis-anilinopyrimidines have been identified as potent inhibitors of the tyrosine kinase EphB4. Structural information from two alternative series identified from screening efforts was combined to identify the initial leads.

Published
2008
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