Synthesis, SAR, and X-ray structure of tricyclic compounds as potent FBPase inhibitors

With the aim of discovering a novel class of fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of compounds based on tricyclic scaffolds was synthesized. Extensive SAR studies led to the finding of 8l with an IC50 value of 0.013 μM against human FBPase. An X-ray crystallographic study revealed that 8l bound at AMP binding sites of human liver FBPase with hydrogen bonding interactions similar to AMP.

Graphical abstractA novel series of tricyclic compounds were designed and synthesized as FBPase inhibitors. SAR studies in this series led to the finding of optimized inhibitors 8l and 14b.Figure optionsDownload full-size imageDownload as PowerPoint slide