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

Bernard Barlaam; Richard Ducray; Christine Lambert-van der Brempt; Patrick Plé; Catherine Bardelle; Nigel Brooks; Tanya Coleman; Darren Cross; Jason G Kettle; Jon Read

doi:10.1016/j.bmcl.2011.03.009

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

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2207-11. doi: 10.1016/j.bmcl.2011.03.009.

Authors

Bernard Barlaam¹, Richard Ducray, Christine Lambert-van der Brempt, Patrick Plé, Catherine Bardelle, Nigel Brooks, Tanya Coleman, Darren Cross, Jason G Kettle, Jon Read

Affiliation

¹ AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims, Cedex 2, France.

PMID: 21441027
DOI: 10.1016/j.bmcl.2011.03.009

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.

MeSH terms

Administration, Oral
Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry*
Aniline Compounds / pharmacokinetics
Animals
Benzyl Alcohol / chemical synthesis
Benzyl Alcohol / chemistry*
Benzyl Alcohol / pharmacokinetics
Binding Sites
Computer Simulation
Crystallography, X-Ray
Drug Evaluation, Preclinical
Mice
Mice, Nude
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

Substances

Aniline Compounds
Protein Kinase Inhibitors
Pyrimidines
Receptor, EphB4
Benzyl Alcohol