Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit.
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Hu E, Tasker A, White RD, Kunz RK, Human J, Chen N, Burli R, Hungate R, Novak P, Itano A, Zhang X, Yu V, Nguyen Y, Tudor Y, Plant M, Flynn S, Xu Y, Meagher KL, Whittington DA, Ng GY
Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit.
J Med Chem. 2008 Jun 12;51(11):3065-8. doi: 10.1021/jm800188g. Epub 2008 May 1.
- PubMed ID
- 18447379 [ View in PubMed]
- Abstract
Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 3-(2-aminoquinazolin-6-yl)-1-(3,3-dimethylindolin-6-yl)-4-methylpyridin-2(1H)-one Vascular endothelial growth factor receptor 2 IC 50 (nM) 48 N/A N/A Details 3-(2-aminoquinazolin-6-yl)-4-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one Vascular endothelial growth factor receptor 2 IC 50 (nM) >5000 N/A N/A Details Imatinib Platelet-derived growth factor receptor alpha IC 50 (nM) 18 N/A N/A Details Imatinib Tyrosine-protein kinase ABL1 IC 50 (nM) 98 N/A N/A Details N'-(6-aminopyridin-3-yl)-N-(2-cyclopentylethyl)-4-methyl-benzene-1,3-dicarboxamide Vascular endothelial growth factor receptor 2 IC 50 (nM) >25000 N/A N/A Details