Design and synthesis of DPP-IV inhibitors lacking the electrophilic nitrile group

A series of (4β-substituted)-l-prolylpyrrolidine analogs lacking the electrophilic nitrile function were synthesized and their dipeptidyl peptidase IV (DPP-IV) inhibitory activity and duration of ex vivo activity were evaluated. Structural optimization of a N-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine analog 8, which was found by high-speed analog synthesis, was carried out to improve the potency and duration of action. A representative compound 26 was evaluated to assess its effect on the plasma glucose level after the oGTT (oral glucose tolerance test) in normal rats. Structure–activity relationships (SAR) are also presented.

A series of 4β-[1-N-(sulfur-containing hetero-aryl)piperazin-4-ylcarbonyl]-l-prolylpyrrolidine analogs were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitor. The duration of ex vivo activity and the effect on the plasma glucose level were evaluated.Figure optionsDownload as PowerPoint slide