[(S)-γ-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) enhancers, are looked to as a potential new class of antidiabetic agents. In particular, potent and long-acting inhibitors might offer advantages in exploiting DPP-IV inhibition. The series of [(S)-γ-(arylamino)prolyl]-(S)-2-cyanopyrrolidine compounds on which we reported previously has a highly potent inhibitory activity but seemed to be unstable in neutral aqueous solution. Here, we describe [(S)-γ-(arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. They are the thiazolidine analogs of [(S)-γ-(arylamino)prolyl]-(S)-2-cyanopyrrolidine but with the electrophilic nitrile removed to improve chemical stability in aqueous solution. Of the compounds investigated in the present study, the [((S)-γ-3,4-dicyanophenylamino)prolyl]thiazolidine 12m was the most potent. The structure–activity relationship (SAR) of the γ-substituent in the proline moiety of the thiazolidide was similar to that obtained with the (S)-2-cyanopyrrolidide. The γ-substituent in the proline moiety of both the (S)-2-cyanopyrrolidide and the thiazolidide may engage with the S2 binding pocket of DPP-IV and thereby achieve hydrophobic interaction in the same manner. Based on pharmacokinetic experiments in rats, the representative compound 11, which displayed high oral bioavailability (BA = 83.9%) and long half-life in plasma (t1/2 = 5.27 h), was found to have an excellent pharmacokinetic profile.

[(S)-γ-(Arylamino)prolyl]thiazolidine compounds were synthesized and evaluated as a novel series of potent and stable DPP-IV inhibitors. The 3,4-dicyanophenylamino-substituted compound 12m showed the most potent inhibitory activity, while the (5-cyano-2-pyridyl)amino-substituted compound 11 exhibited an excellent pharmacokinetic profile.Figure optionsDownload as PowerPoint slide