title: Novel inhibitors of VEGF receptors-1 and -2 based on azole-5-carboxamide templates.
abstract: We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases VEGFR-2 and -1. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib(trade)) and ZD6474 (Vandetanib(trade mark)). High permeability of active compounds across the Caco-2 cell monolayer (>40 x 10(-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. ask@chemdiv.com <ask@chemdiv.com>
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Daniel
authors.initials: D
authors.lastname: Milligan
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ouyang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000577:Amides / Q000737:chemistry*; D001393:Azoles / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010793:Phthalazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D000577:Amides; D001393:Azoles; D010793:Phthalazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; C404768:vatalanib; D000255:Adenosine Triphosphate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib