2‑Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4

As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities be...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2018-03, Vol.9 (3), p.215-220
Main Authors: Knoepfel, Thomas, Furet, Pascal, Mah, Robert, Buschmann, Nicole, Leblanc, Catherine, Ripoche, Sebastien, Graus-Porta, Diana, Wartmann, Markus, Galuba, Inga, Fairhurst, Robin A
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Language:English
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Letter
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Summary:As part of a project to identify FGFR4 selective inhibitors, scaffold morphing of a 2-formylquinoline amide hit identified series of 2-formylpyridine ureas (2-FPUs) with improved potency and physicochemical properties. In particular, tetrahydronaphthyridine urea analogues with cellular activities below 30 nM have been identified. Consistent with the hypothesized reversible-covalent mechanism of inhibition, the 2-FPUs exhibited slow binding kinetics, and the aldehyde, as the putative electrophile, could be demonstrated to be a key structural element for activity.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00485