Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines.
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.
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Catherine
C
Bardelle
Tanya
T
Coleman
Darren
D
Cross
Sara
S
Davenport
Jason G
JG
Kettle
Eun Jung
EJ
Ko
Andrew G
AG
Leach
Andrew
A
Mortlock
Jon
J
Read
Nicola J
NJ
Roberts
Peter
P
Robins
Emma J
EJ
Williams
D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D036224:Receptor, EphB4