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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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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cited_by cdi_FETCH-LOGICAL-a523t-e8fe91b6dc92dfecf17a1208410a85068cde8fd559a3d718423ce1632a116cf23
cites cdi_FETCH-LOGICAL-a523t-e8fe91b6dc92dfecf17a1208410a85068cde8fd559a3d718423ce1632a116cf23
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container_title ACS medicinal chemistry letters
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creator Knoepfel, Thomas
Furet, Pascal
Mah, Robert
Buschmann, Nicole
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Fairhurst, Robin A
description 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.
doi_str_mv 10.1021/acsmedchemlett.7b00485
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title 2‑Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4
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