Discovery of imidazole vinyl pyrimidines as a novel class of kinase inhibitors which inhibit Tie-2 and are orally bioavailable.
Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.
Buttar
David
D
Cancer and Infection Research Area, Mereside, Alderley Park, AstraZeneca, Macclesfield SK10 4TG, UK.
Edge
Mike
M
Emery
Steve C
SC
Fitzek
Martina
M
Forder
Cheryl
C
Griffen
Alison
A
Hayter
Barry
B
Hayward
Chris F
CF
Hopcroft
Philip J
PJ
Luke
Richard W A
RW
Page
Ken
K
Stawpert
John
J
Wright
Andy
A
D000284:Administration, Oral; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D042787:Receptor, TIE-2; C030986:pyrimidine