Irreversible Inhibition of Dipeptidyl Peptidase 8 by Dipeptide-Derived Diaryl Phosphonates

摘要

Dipeptide-derived compounds,bearing various P2 residues and a diaryl pyrrolidin-2-yl phosphonate at the P1 position,were evaluated as dipeptidyl peptidase 8(DPP8)inhibitors.With these products,irreversible inhibition of DPP8 was observed.To obtain inhibitors with an improved activity and selectivity profile,a set of selected analogues containing a diaryl isoindolin-1-ylphosphonate at P1 was synthesized and evaluated.Within this latter series,compound 2e was shown to be a potent,irreversible inhibitor of DPP8,demonstrating very low affinity for DPP IV and DPP II.