[(S)-γ-(4-Aryl-1-piperazinyl)-l-prolyl]thiazolidines as a novel series of highly potent and long-lasting DPP-IV inhibitors

In the search for an inhibitor of dipeptidyl peptidase IV (DPP-IV) highly potent both in vitro and in vivo, we synthesized a series of l-prolylthiazolidine-based DPP-IV inhibitors having 4-arylpiperazine or 4-arylpiperidine at the γ-position of the proline structure. Of these compounds, the 4-(5-nitro-2-pyridyl)piperazine analog 21e showed a sub-nanomolar (IC50 = 0.92 nmol/L) DPP-IV inhibitory activity and a long-lasting in vivo DPP-IV inhibition profile.

Graphical abstractBy introducing 4-arylpiperazine into the γ-position of l-proline structure, 21e shows a sub-nanomolar (IC50 = 0.92 nmol/L) DPP-IV inhibitory activity despite the lack of an electrophilic trap at the P1 position.Figure optionsDownload full-size imageDownload as PowerPoint slide