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.
Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK. richard.luke@astrazeneca.com
Richard W A
RW
Luke
Peter
P
Ballard
David
D
Buttar
Leonie
L
Campbell
Jon
J
Curwen
Steve C
SC
Emery
Alison M
AM
Griffen
Lorraine
L
Hassall
Barry R
BR
Hayter
Cliff D
CD
Jones
William
W
McCoull
Martine
M
Mellor
Mike L
ML
Swain
Julie A
JA
Tucker
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