title: ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2.
abstract: We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
authors.affiliation: Small Molecule Drug Discovery, Chemical Diversity, Inc., 11558 Sorrento Valley Road, San Diego, CA 92121, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Evgueni L
authors.initials: EL
authors.lastname: Piatnitski
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Samet
authors.forename: Victor P
authors.initials: VP
authors.lastname: Kisliy
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001393:Azoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D001393:Azoles; D000255:Adenosine Triphosphate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2