ABSTRACT
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Subject(s)
Phthalazines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Female , Isoquinolines/chemical synthesis , Isoquinolines/pharmacokinetics , Mice , Mice, Inbred Strains , Phthalazines/administration & dosage , Phthalazines/chemical synthesis , Piperidines , Quinazolines , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitorsABSTRACT
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Subject(s)
Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Azepines/pharmacology , ErbB Receptors/antagonists & inhibitors , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Antineoplastic Agents/pharmacology , Azepines/chemistry , Cell Line, Tumor , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Inhibitory Concentration 50 , Neoplasm Proteins/antagonists & inhibitors , Phosphorylation/drug effects , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Subject(s)
Isoquinolines/pharmacology , Phthalazines/pharmacology , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Fluoroimmunoassay , Humans , Inhibitory Concentration 50 , Isoquinolines/chemical synthesis , Phthalazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A novel class of 4-arylamino-phthalazin-1-yl-benzamides is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display potent VEGFR-2 inhibitory activity with an IC50 as low as 0.078 microM in an HTRF enzymatic assay. These compounds are relatively selective against a small kinase panel.
