Synthesis and evaluation of structurally constrained imidazolidin derivatives as potent dipeptidyl peptidase IV inhibitors

To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine derivatives with constrained imidazolidin ring and tested their activities against DPP-IV. Most of them exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound among these is (S)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxoimidazolidin-1-yl)ethyl-amino)acetyl)pyrrolidine-2-carbonitrile (6n), which is a 2 nM DPP-IV inhibitor.

R = 3,4-Dimethoxyphenyl, DPP-IV IC50 = 2.0 nMFigure optionsDownload as PowerPoint slide