Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo.
The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.
Luke
Richard W A
RW
Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK. richard.luke@astrazeneca.com
Ballard
Peter
P
Buttar
David
D
Campbell
Leonie
L
Curwen
Jon
J
Emery
Steve C
SC
Griffen
Alison M
AM
Hassall
Lorraine
L
Hayter
Barry R
BR
Jones
Cliff D
CD
McCoull
William
W
Mellor
Martine
M
Swain
Mike L
ML
Tucker
Julie A
JA
D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C476003:thienopyrimidine; D042787:Receptor, TIE-2