Evaluation of indazole-based compounds as a new class of potent KDR/VEGFR-2 inhibitors.
A novel class of potent and selective inhibitors of KDR incorporating an indazole moiety 1 is reported. The discovery, synthesis, and structure-activity relationships of this series of inhibitors have been investigated. The most promising compounds were also profiled to determine their pharmacokinetic properties and evaluated in a VEGF-induced vascular permeability assay.
Bauer
David
D
Department of Medicinal Chemistry, Amgen, Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA.
Whittington
Douglas A
DA
Coxon
Angela
A
Bready
James
J
Harriman
Shawn P
SP
Patel
Vinod F
VF
Polverino
Anthony
A
Harmange
Jean-Christophe
JC
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2