Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors

A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.

Graphical abstractA series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment based drug discovery. The lead compounds showed KHK enzyme activity in the nM range with amendable pharmaceutical properties.Figure optionsDownload full-size imageDownload as PowerPoint slide