title: Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships.
abstract: The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the "angiogenic switch," is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.
authors.affiliation: Bayer Research Center, Bayer Corporation, Pharmaceutical Division, 400 Morgan Lane, West Haven, CT 06516, USA. stephen.boyer.b@bayer.com
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Boyer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D016228:Endothelial Growth Factors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D000255:Adenosine Triphosphate; D040301:Vascular Endothelial Growth Factor Receptor-2