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Tetrahedron Lett. 2011 Apr 27;52(17):2228-2231.

Aryl Extensions of Thienopyrimidinones as Fibroblast Growth Factor Receptor 1 Kinase Inhibitors.

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Department of Chemistry, Yale University, New Haven, Connecticut 06520.


Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl subtituent can be introduced at the 2-position in strucure 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 here, 13, has a 4-hydroxyphenyl substituent and yields an IC(50) 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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