Aryl Extensions of Thienopyrimidinones as Fibroblast Growth Factor Receptor 1 Kinase Inhibitors |
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Authors: | Ekkati Anil R Madiyan Valsan Ravindranathan Krishna P H Bae Jae Schlessinger Joseph Jorgensen William L |
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Institution: | a Department of Chemistry, Yale University, New Haven, CT 06520, United States b Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States |
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Abstract: | Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl substituent can be introduced at the 2-position in structure 3. The substituent is anticipated to project deeper into the binding site and provide opportunities for enhanced activity and selectivity. The most potent analog reported herein, 13, has a 4-hydroxyphenyl substituent and yields an IC50 of 6 μM for inhibition of phosphorylation by FGFR1 kinase. It was also found that the western anisole-containing substituent in 3 can be replaced by a propionic acid group with no loss in potency and with potentially significant gains in pharmacologically relevant properties. |
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Keywords: | FGFR1 kinase inhibitors Structure-based inhibitor design Thienopyrimidinones ATP-competitive small molecule inhibitors |
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