2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4
2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4
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DOI：
10.1021/acsmedchemlett.7b00485
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发表时间：
2018-03-01
影响因子：
4.2
通讯作者：
Fairhurst, Robin A.
中科院分区：
文献类型：
--
作者：
Knoepfel, Thomas;Furet, Pascal;Fairhurst, Robin A.
作为鉴定FGFR 4选择性抑制剂的项目的一部分，2-甲酰基喹啉酰胺的支架变形击中了鉴定的一系列具有改善的效力和物理化学性质的2-甲酰基吡啶脲（2-FPU）。特别地，已经鉴定了具有低于30 nM的细胞活性的四氢萘啶脲类似物。与假设的可逆-共价抑制机制一致，2-FPU表现出缓慢的结合动力学，醛作为推定的亲电体，可以证明是活性的关键结构元素。
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.