Discovery of dipeptidyl peptidase IV (DPP4) inhibitors based on a novel indole scaffold

Dipeptidyl peptidase IV (DPP4) inhibitors are proven in the treatment of type 2 diabetes. We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9 (DPP9) (>200 fold). We further co-crystallized DPP4 with indole sulfonamide (compound 1) to confirm a proposed binding mode. Good metabolic stability of the indole compounds represents another positive attribute for further development.

Graphical abstractThe story of our effort in the de novo design and development of a series of potent and selective DPP4 inhibitors based on an indole scaffold utilizing structure-based drug design (SBDD) technology.Figure optionsDownload full-size imageDownload as PowerPoint slide