A prodrug approach towards the development of tricyclic-based FBPase inhibitors

For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.

Graphical abstractIntroduction of pyridine-containing prodrug moieties into tricyclic-based FBPase inhibitors led to the discovery of prodrug 20, which showed reduced CYP3A4 inhibitory potency compared to diamide prodrug 4.Figure optionsDownload full-size imageDownload as PowerPoint slide