Novel triazolopyridylbenzamides as potent and selective p38α inhibitors

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.

Graphical abstractThe use of structure-based design and molecular modeling led to the discovery of triazolopyridylbenzamide derivatives as potent and selective p38α inhibitors. An X-ray complex of the ligand with p38α showed an unprecedented binding mode.Figure optionsDownload full-size imageDownload as PowerPoint slide