Lead optimization of [(S)-γ-(arylamino)prolyl]thiazolidine focused on γ-substituent: Indoline compounds as potent DPP-IV inhibitors

Dipeptidyl peptidase IV (DPP-IV) inhibitors are looked to as a potential new antidiabetic agent class. A series of [(S)-γ-(arylamino)prolyl]thiazolidine compounds in which the electrophilic nitrile is removed are chemically stable DPP-IV inhibitors. To discover a structure for the γ-substituent of the proline moiety more suitable for interacting with the S2 pocket of DPP-IV, optimization focused on the γ-substituent was carried out. The indoline compound 22e showed a DPP-IV-inhibitory activity 100-fold more potent than that of the prolylthiazolidine 10 and comparable to that of NVP-DPP728. It also displayed improved inhibitory selectivity for DPP-IV over DPP8 and DPP9 compared to compound 10. Indoline compounds such as 22e have a rigid conformation with double restriction of the aromatic moiety by proline and indoline structures to promote interaction with the binding site in the S2 pocket of DPP-IV. The double restriction effect provides a potent inhibitory activity which compensates for the decrease in activity caused by removing the electrophilic nitrile.

Lead optimization of the DPP-IV inhibitor [(S)-γ-(arylamino)prolyl]thiazolidine was conducted with focus on the γ-substituent. Compounds with an indoline structure at the γ-position showed potent activity, with the representative compound 22e 100-fold more potent than the prolylthiazolidine 10 and comparable to NVP-DPP728 despite its lack of an electrophilic group.Figure optionsDownload as PowerPoint slide