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.

中文翻译：

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2-甲酰基吡啶基尿素是成纤维细胞生长因子受体的高度选择性可逆共价抑制剂4。

作为鉴定FGFR4选择性抑制剂的项目的一部分，对2-甲酰基喹啉酰胺的支架进行了热定型，从而鉴定出一系列具有更高效价和理化特性的2-甲酰基吡啶尿素（2-FPU）。特别地，已经鉴定了具有低于30nM的细胞活性的四氢萘啶脲类似物。与假定的抑制性可逆共价机制一致，2-FPUs的结合动力学较慢，醛（作为假定的亲电试剂）可被证明是活性的关键结构要素。