Optimization of triarylimidazoles for Tie2: influence of conformation on potency.
In an effort to understand the effect of N-alkylation of triarylimidazoles on Tie2 inhibition, ortho-substituted C-2 aryl analogs were synthesized to investigate the effect of different torsion angles on potency. This exercise resulted in the identification of a potent and selective tetrasubstituted imidazole that was efficacious in an animal model of angiogenesis.
Johnson
Neil W
NW
GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. neil.w.johnson@gsk.com
Semones
Marcus
M
Adams
Jerry L
JL
Hansbury
Michael
M
Winkler
Jim
J
D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship