title: 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2.
abstract: Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
authors.affiliation: deCODE, 2501 Davey Road, Woodridge, IL 60616, USA. akiselyov@decode.com
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Marina
authors.initials: M
authors.lastname: Semenova
authors.forename: Victor V
authors.initials: VV
authors.lastname: Semenov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D018938:Caco-2 Cells; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009841:Oligonucleotides; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D009841:Oligonucleotides; D010793:Phthalazines; D011725:Pyridines; D013844:Thiazoles; D009536:Niacinamide; C404768:vatalanib; D000255:Adenosine Triphosphate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C519562:imetelstat