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.

The 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 as PowerPoint slide