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

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 8; pp. 2207 - 2211
• Main Authors: Barlaam, Bernard, Ducray, Richard, Brempt, Christine Lambert-van der, Plé, Patrick, Bardelle, Catherine, Brooks, Nigel, Coleman, Tanya, Cross, Darren, Kettle, Jason G., Read, Jon
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.04.2011; Elsevier
• Subjects: Administration, Oral; Analytical, structural and metabolic biochemistry; Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacokinetics; Animals; Benzyl Alcohol - chemical synthesis; Benzyl Alcohol - chemistry; Benzyl Alcohol - pharmacokinetics; Binding Sites; Biological and medical sciences; Bis-anilinopyrimidine; Computer Simulation; Crystallography, X-Ray; Drug Evaluation, Preclinical; Enzymes and enzyme inhibitors; EphB4 kinase; Fundamental and applied biological sciences. Psychology; Kinase inhibitor; Medical sciences; Mice; Mice, Nude; Miscellaneous; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Receptor, EphB4 - antagonists & inhibitors; Receptor, EphB4 - metabolism; Structure-Activity Relationship; Transferases; EphB4 kinase; Kinase inhibitor; Bis-anilinopyrimidine; Intravenous administration; Rat; Nitrogen heterocycle; Morpholine derivatives; Modeling; Signal transduction; Structure activity relation; Molecular model; Receptor protein-tyrosine kinase; Chemical synthesis; Dog; Oxygen nitrogen heterocycle; Fissipedia; Carnivora; Enzyme; Transferases; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; Aniline derivatives; In vitro; Primary alcohol; In vivo; Vertebrata; Mammalia; Mouse; Animal; Pyrimidine derivatives; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.03.009

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.