Design, Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors

Main observation and conclusion Dipeptidyl peptidase 4 (DPP‐4) is a clinically validated target for the treatment of type 2 diabetes mellitus (T2DM). To discover novel and potent DPP‐4 inhibitors, three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2‐phenyl‐3,4‐dihydro‐2H‐benzo[f]chromen‐3‐amine. Among the designed compounds, 41d‐1 was the most potent one with an IC50 value of 16.00 nM. Besides, 41d‐1 (5 mg/kg) displayed a moderate glucose tolerance capability in ICR mice. Structure‐activity‐relationship (SAR) studies were discussed in detail, which is constructive for our further optimization. A novel DPP‐4 inhibitor 41d‐1 was based on the scaffold of dihydrobenzo[f]thiochromen amine with an IC50 value of 16.00 nM.