3,4-Disubstituted isothiazoles: Novel potent inhibitors of VEGF receptors 1 and 2

• Published in: Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (4), p.1195-1198
• Main Authors: Kiselyov, Alexander S., Semenova, Marina, Semenov, Victor V.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Angiogenesis; ATP-competitive kinase inhibitors; Caco-2 Cells; Combinatorial Chemistry Techniques; Drug Design; Humans; Indoles - pharmacology; Isothiazoles; Molecular Structure; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phthalazines - pharmacology; Pyridines - pharmacology; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Vascular endothelial growth factor receptor 2; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.12.078

Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed both good potency (27–41 nM) and 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. 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 × 10 −5 cm/min) across Caco-2 cell monolayer.