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

Catherine Bardelle; Tanya Coleman; Darren Cross; Sara Davenport; Jason G Kettle; Eun Jung Ko; Andrew G Leach; Andrew Mortlock; Jon Read; Nicola J Roberts; Peter Robins; Emma J Williams

doi:10.1016/j.bmcl.2008.09.087

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

Bioorg Med Chem Lett. 2008 Nov 1;18(21):5717-21. doi: 10.1016/j.bmcl.2008.09.087. Epub 2008 Sep 27.

Authors

Catherine Bardelle¹, Tanya Coleman, Darren Cross, Sara Davenport, Jason G Kettle, Eun Jung Ko, Andrew G Leach, Andrew Mortlock, Jon Read, Nicola J Roberts, Peter Robins, Emma J Williams

Affiliation

¹ AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.

PMID: 18851911
DOI: 10.1016/j.bmcl.2008.09.087

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.

MeSH terms

Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, EphB4 / antagonists & inhibitors*

Substances

Protein Kinase Inhibitors
Pyrimidines
Receptor, EphB4