Abstract
A series of isothiazolopyrimidines and isoxazolopyrimidines were synthesized and identified as potent KDR inhibitors. SAR studies led to isothiazolopyrimidine urea analogs that potently inhibit VEGFR tyrosine kinases (KDR enzymatic and cellular IC(50) values below 10 nM) as well as cKIT and TIE2. The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively.
MeSH terms
-
Administration, Oral
-
Animals
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Inhibitory Concentration 50
-
Kinetics
-
Mice
-
Models, Chemical
-
Models, Molecular
-
Proto-Oncogene Proteins c-kit / metabolism
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacology
-
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Receptor Protein-Tyrosine Kinases / chemistry
-
Receptor, TIE-2 / metabolism
-
Structure-Activity Relationship
-
Vascular Endothelial Growth Factor Receptor-1 / metabolism
Substances
-
Enzyme Inhibitors
-
Pyrimidines
-
Proto-Oncogene Proteins c-kit
-
Receptor Protein-Tyrosine Kinases
-
Receptor, TIE-2
-
Vascular Endothelial Growth Factor Receptor-1